Part I: The Neuron, Action Potentials and Neurotransmitters
A neuron is made up of a nucleus surrounded by a soma. This soma is filled with the cytosol and contains the endoplasmic reticulum, mitochondria, Golgi bodies and polyribosomes, among other things. It is surrounded by a neuronal membrane. At certain points, it branches out into axons, which transmit the nerve signals. At the axon hillock, the point where the axon leaves the soma, there are microtubules that help propel materials into the axon to and from the nerve terminal. This is called axoplasmic transport; anterograde axoplasmic transport uses kinesin proteins and walks materials from the soma to the terminal, and retrograde axoplasmic transport uses dynein proteins to transport materials the other way. The axon meets the synapse, an area where transmission of signal occurs (usually at the dendrite), at the synaptic junction, with the presynaptic axon terminal on the axon and the postsynaptic dendrite on the dendrite side. Synaptic vesicles in the active zones on the axon terminal, or neurosecretion zone, contain the neurotransmitter to be transmitted; receptors in the synaptic cleft of the dendrite bind the neurotransmitter peptides and proteins.
The axon is usually surrounded by myelin, which assists in speeding transmission of nerve signals by reducing leakage. Saltatory conduction occurs at the unmyelinated areas do exist on the axon, like at the nodes of Ranvier, where most voltage gated sodium channels exist. Disruption of the myelin can lead to limb injury from neglect of infection, like in leprosy and other diseases that affect either the Schwann cells or the oligodendrocytes, which myelinate the PNS and CNS respectively. The neuron itself is surrounded by glia, which include the Schwann cells, oligodendrocytes and the astrocytes, which helps maintain neuron structure and placement, take up excess potassium and restrict the spread of neurotransmitter by restricting synaptic junctions.
The resting potential is the difference in electrical charge across the membrane, which is usually at around -65 mV. It can be changed by the use of ion channels and pumps. Equilibrium potentials differ for each of the ions. Potassium RP occurs at -80 mV; calcium at +123 mV, chloride ion at -65 mV and sodium at +62 mV. Depolarization occurs as the potential is made more negative, and hyperpolarization occurs as the opposite. The potential can be calculated using the Nernst equation, which in simple form, says: E = 61.54 mV log ([Xo] /[Xi]). The Goldman equation includes the relative conc. of ions that contribute: V = 61.54 mV log ((Pk [Ko} + Pna [Nao])/ ((Pk [Ki} + Pna [Nai])).
The action potential lasts 2 milliseconds and is a one-shot, non-decaying signal that travels from the hillock outwards. It is made up of a rising phase, where sodium entry starts to depolarize the cell. It passes a threshold of -20 mV and heads to the overshoot, which is around +40 mV. After a 1 millisecond delay, or the absolute refractory period, in which the sodium membranes are quickly stopped and potassium membranes are opened, during the relative refractory period, immediately after, the current needed to activate a potential is increased. The inactivation of the sodium pumps prevents signals from going backwards along the axon. Also, the potential can start anywhere along the axon, but only precedes in one direction. Then, the falling phase occurs. Entry of potassium repolarizes the membrane. The undershoot is where the potential actually dips underneath the normal resting potential toward potassium equilibrium. Conduction veolicty can be increased by increasing axonal diameter. At the same time, increases in axonal size can decrease the strength of the depolarization.
Voltage gated sodium channels (and similarly, the voltage gated potassium channels) are controlled by voltage changes and are selective for sodium, by use of a selectivity filter that must recognize and strip off a water �chaperone� molecule that is necessary. It is a polypeptide with four domains of six alpha helices each. It opens with a little delay for a millisecond and then closes with the overshoot until the V is neagitve again. These channels can be clogged up using poisons such as TTX, which clogs the sodium permeable pore; TEA, which does the same for K pores; and cyanide, which blocks the sodium potassium pump. K channels also have delayed rectifiers which, after a millisecond delay, reset V.
The 1903 Nobel Prize was shared by Golgi and Cajal, who were bitter competitors on the discussion of communication in neurons. It was thought by Golgi that there was full physical contact, but Cajal believed in the neuron doctrine that argued that it was more proximity than full physical contact. Later research discovered electrical synapses, which occurred at gap junctions. These junctions were spanned by connexins, or a stack of connexon proteins, that formed a bridge for ions to pass over. Their diameter was around 2-3 nm and offered bi-directional and instantaneous signal transmission that was used most often for fight or flight reflexes. Helmholtz studied the relation of nerve conduction velocity to temperature and electrical stimulation. Other studies confirmed the existence of chemical synapses on top of the electrical route. Loewi, by collecting electrically stimulated heart bathing solution and proving that it could stimulate similar reactions in another heart, showed that there was a chemical basis for neuron transmission. He named the material vagusstoff (because it came from stimulation of the vagal nerve), which was later found to be acetylcholine. He was lucky in reaching these conclusions; he performed the experiment in the spring, when acetylcholinesterase was low, and thus results weren�t misleading. A later experiment showed that blockage of chemical signals could also occur at the receptors and not just at the neurotransmitter production sites, as Bernard did with curare and frog neuromuscular junctions.
Chemical synapses occurs by axon terminal secretion and transmission of neurotransmitter into the synapse, at the synaptic cleft, which spans 20-50 nm. Secretory granules and synaptic vesicles contain the neurotransmitters; these have certain qualifications: ability to concentrate neurotransmitter within itself, quantal amounts of neurotransmitter, ability to synthesize and ability to prevent degradation. Comparatively the neurotransmitter required in the body is much more than the brain. In the body, an overwhelming stimulus ensures the action is done, but overload of the brain is a problem, so stimulation is much less in the brain. Neurotransmitter types include amino acids, which include gamma-butyric acid or GABA, glutamine, and glycine; amines, which include acetylcholine, epinephrine, norepinephrine and serotonin; and peptides, such as cholecystokinin or CCK and somatostatin. Peptides are better classified as neuromodulators, because they bind and can mediate self-release. Neurotransmitters must have a function, must be calcium dependent for release, must have a receptor and have some way to inactivate it. After neurotransmitters bind to receptors in the active zone (peptides are released elsewhere), they are destroyed, taken up by surrounding cells or reloaded into vesicles to be taken back to the nerve terminal, which also can be recycled by reinsertion into the neuronal membrane.
The synapse occurs as follows:
1) action potential triggers voltage gated calcium channels
2) calcium binds to calmodulin which activates kinases, which in turn activate synapsins, including synaptotagmins, which work with binding and fusion by creating scaffolding
3) V-SNARE (on vesicle, c-terminus in cytoplasm) and T-SNARE (in active zone) proteins bind to lock release site, and then vesicle fuses
4) Exocytosis or transmitter release
5) Endocytosis or vesicle recovery
Synapses are categorized as axodendritic, axosomatic, axoaxonic, and dendrodendritic. In the CNS, there are two types: 1) Gray�s Type I, which are of different thicknesses and usually run excitatory post-synpatic potentials (EPSP), and 2) Gray�s Type II, which are of similar thicknesses and run inhibitory post-synaptic potentials (IPSP).
Modern receptor theory was set down by Langly, who argued that receptors must be able to do two things: bind neurotransmitters with high affinity and promote effector action through this binding. Antagonists are proteins that can bind to receptors to block the site and produce no response. Agonists meanwhile are neurotransmitter mimics that produces some response after binding. Receptors include transmitter gated ion channels. These channels are made up of 4-5 subunits which are embedded in the membrane; these get activated after the transmitter �key� opens the channel �lock�. These are graded potentials. Acetylcholine and glutamate gated channels are associated with cationic sodium depolarization that brings the potential closer to the action potential threshold. The fulminatory effect is known as the EPSP. The IPSP is brought about by anionic chlorine hyperpolarization associated with glycine and GABA gated channels. These channels are not so ion selective and transmit within 100-200 milliseconds. Spatial summations are the summation of simultaneously generated EPSP�s at different synapses, while temporal summation is the addition of EPSP�s generated in rapid succession at the same synapse.
G-protein coupled receptors are slower and have a longer lasting action. It works by binding membrane receptors which then activate G-proteins, which activate effector proteins which either lead to ion channels or are second messengers that can modulate neurotransmitter release. They are made of 7 subunits which exist in 3 loops that pop in and out of the membrane. The 3rd loop is usually largest and most complicated. The larger molecules tend to bind outside and the smaller ones deeper inside the membrane. The G-protein process works by starting out with the alpha, beta and gamma subunits, with GDP attached. The GDP is released and GTP bound; right after that, the alpha subunit and GTP break off and can stimulate effector action. The alpha subunit can itself act to break down GTP and then recombine with the other subunits, forming the beginning G-protein again. The cycle usually includes a primary molecule, a transducer, amplifier, precursor, 2nd messenger, and finally an effector. The cAMP cycles includes dopamine, the G-protein, adenylyl cyclase, ATP, which A.C. breaks down into cAMP, which then activates protein kinase A and the signal cascades. The DAG cycles consists of G-protein Q, then phospholipase C, which cuts PIP2 into DAG and IP3. DAG activates protein kinase C, while IP3 activates calcium release in the sarcoplasmic reticulum, which then activates calcium dependent protein kinases.
Part II: Organization of the Nervous System
The central nervous system (CNS) is made up of the brain and the spinal cord. The brain can be seen using anterior/posterior views (front/back), or medial/lateral (close/far away from midline), or dorsal/ventral (top/bottom), or the midsagittal, horizontal and coronal planes. The midsagittal fissure splits the brain into two hemispheres, left and right. The horizontal plane is parallel to the ground, and the coronal plane is perpendicular to the ground. Common to all mammalian brains are the cerebrum, cerebellum and the brain stem. The cerebrum is the largest part of the brain and controls the higher function. It is normally split into the frontal lobe, the parietal lobe (separated by the central sulcus), then the temporal lobe and occipital lobe beneath the other two. The cerebral cortex is arranged in sheets of neurons and is differentiated. The hippocampus has one cell layer; the olfactory cortex is continuous with the olfactory bulb; and the neocortex, which has many cell layers. The neocortex cytoarchitectural map was put together by Brodmann, and his rules state that there are six layers all over the cortex.
Directly behind it is the cerebellum, which controls balance, posture and movement, and the brain stem, made of the pons and medulla, which control involuntary reactions like breathing, consciousness, body temperature and heart rate. Specifically, the pons serves as a switchboard connecting the cerebral cortex to the cerebellum. The axons that don�t go to the pons go instead to the medulla, where a crossing over occurs. This explains why one side of the brain controls movements on the other. From the brain stem come 12 cranial nerves that innervate the brain, including motor nerves, sensory nerves (optic nerve), and combinatory nerves (the vagus). During brain development, the brain is differentiated into the forebrain, midbrain and hindbrain. The forebrain gives rise to the diencephalon and telencephalon, which in turn give rise to the optic system, the hypothalamus (which controls fight or flight via the visceral PNS), the thalamus, the third ventricle, and the corpus callosum, which forms an axonal bridge over the 2 cerebral hemispheres. The dorsal thalamus is an important section of the forebrain, as it lies in the path of most of the sensory pathways. The midbrain contains the tectum, which gives rise to the superior colliculus (receives direct visual input, controls eye movements) and inferior colliculus (ditto, for the ear), as well as the tegmentum, which contains the substantia nigra and the red nucleus (involved in voluntary movement) and the cerebral aqueduct, part of the ventricular system. Finally, the hindbrain contains the brain stem and the fourth ventricle, which is continuous with the cerebral aqueduct.
The brain as a whole is covered by the meninges, made of three membranes, known as the pia mater (a soft shell), arachnoid membrane and dura mater (the hard outer layer), with the subarachnoid and subdural spaces in between. Within these spaces are a salty clear liquid known as cerebrospinal fluid (CSF). The ventricular system of the brain contains this fluid, made by the choroid plexus. The brain can be imaged using computed tomography (CT) scans, magnetic resonance imaging (MRI), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI).
The spinal cord is attached to the brain stem and runs down the vertebral column; it is the conduit of info to and from the skin, joints and muscles to the brain. Communication goes via the 30 spinal nerves, which exit the spinal cord from in between each vertebra, through the dorsal (toward the back) and ventral roots (toward the belly). These nerves are part of the somatic peripheral nervous system, as are the motor and sensory axons that enter via the roots. Additionally, they are referred to as afferent (to) and efferent (from). The other half of the peripheral nervous system (PNS) is the visceral PNS or autonomic nervous system, that is made up of the neurons that innervate the internal organs, blood vessels and glands. These include neurons that help in the sympathetic (fight or flight response) or the parasympathetic (vegetative) response. Neurons within the PNS are referred to as ganglia; axon bundles are called nerves. In the CNS, they are known as grey matter - where the cell bodies are - and white matter, the axons. In the brain, grey matter is the outer layer, but it is the opposite in the spinal cord.
Part III: Olfaction and Gustation
The basic tastes are salt, sour, sweet or bitter - sugars occur naturally, as do some bitter substances, like potassium ions and caffeine. We taste through a combination of the taste and the smell, utilizing the texture, temperature, and pain sensations, as well as the binding of taste receptor cells. Up to 250,000 of these cells are arranged on the taste buds, which exist on the papillae or bumps of the tongue (in foliate or ridge, vallate or pimply, and fungiform or mushroom form). Taste cells make up 1% of the epithelium; the rest are basal cells and afferent axons. Typically, one will have around 5000 taste buds. The bitter area occurs to the back of the tongue; the sour areas are on both sides in the middle, the salty areas are on the sides in front of the sour regions, and the sweet area is right at the tip of the tongue. Papillae (thus, the taste cells) are usually sensitive to one taste, but at higher concentrations, the papillae become less selective. Activation of these cells causes a polarization that must reach a threshold concentration of stimulus - this is graded - before an action potential can cause voltage-gated mediated transmitter release. The transmitter then excites the postsynaptic sensory axon and causes it to fire action potentials toward the brain stem. Complex tastes are mediated by strength of the signal.
Transduction in gustation requires binding of a tastant stimuli, which activates ion channels and second messenger systems to achieve transmitter release. Saltiness comes from the activation of calcium channels by the influx of sodium ions through amiloride sodium channels, which are not voltage-dependent and always stay open. Sourness comes from the calcium-release depolarization effect of hydrogen, which comes directly, or from hydrogen blockage of potassium channels. The strength of the signal reminds the body that it is important to reject harmful stuff. Sweetness comes from the binding of sucrose to the G-protein (gustducin) cAMP second messenger system to activate and block the K channels using PKA. Other passages use the G-protein phospholipase C second-messenger system. Bitterness (poison detector function) can either bind and block potassium channels to force depolarization, or activate the G-protein phospholipase C second-messenger system. Umami, or amino acid, uses glutamate to activate sodium and calcium channels for depolarization or to bind G-protein receptors. Gustatory axons go to, from axon placement in front to back of the tongue, the facial nerve (cranial nerve 7), the glossopharyngeal nerve (cranial nerve 9) and the vagus nerve (cranial nerve 10). From here, they first synapse at the gustatory nucleus, part of the solitary nucleus in the medulla, as converged sense neurons- there are no individual taste neurons. Neural changes can produce behavioral changes here. A separate projection goes to the hypothalamus, to determine when and what to eat, and to the pontine parabrachial nucleus, for autonomic reflexes to taste and taste perception. Second order neurons then synapse locally, and are involved in emesis. From the solitary nucleus, signals travel to the ventral posterior medial nucleus (VPM) in the thalamus, and then to the primary gustatory cortex in Brodmann�s area 36.
Smell not only brings indirect news of the proximity of a substance, but direct chemical signals of behavior, through pheromones, which goes through the vomeronasal organ to affect the accessory olfactory bulb and system. We �smell� using the olfactory epithelium, containing olfactory receptor cells, supporting cells (like glia; produce mucus), and basal cells (make new receptor cells). Odorants (thousands exist) dissolve in the mucus and bind to the membrane receptor proteins (which can recognize multiple odorants) on the cilia that are connected to the dendrite of the olfactory receptor neurons. Transduction follows the G-protein (Golf) cAMP second messenger system that stimulates depolarization by eventually allowing in sodium and calcium and releasing chloride ions through calcium-activated chloride channels. This promotes firing of an action potential down the unmyelinated axons, collectively called the olfactory nerve (cranial nerve I), on the other side of the receptor cell. Axon clusters penetrate the cribriform plate and then connect to the olfactory bulb. This bypasses the usual medulla to thalamus route. Olfactory response terminates after odorant adaptation, break down, or activation of other signaling pathways. After entering the olfactory bulb, they interact with the glomeruli, which usually receives input from only one type of receptor protein. Differentiation is done through modification and modulation by inhibitory and excitatory interactions between bulbs and higher level axon systems. They then pass through the olfactory tract before going to the olfactory tubercle, the medial dorsal (MD) nucleus of the thalamus and then the orbitofrontal cortex. Conversely, they can travel to the hippocampus in the temporal lobe for learning and memory.
Broad tuning is the sampling over populations to interpret a single signal. Population coding, which aligns to the number of general responses rather than a small number of precise signals, is probably used in both taste and smell. Temporal coding, for smell, depends on the timing of spike patterns to determine quality of odors. Parallel processing is also important - taste info is kept separate until it is finally synapsed higher up in the brain. This forms a rudimentary olfactory map.
Part IV: Audition and the Vestibulary System
Sounds are audible variations in air pressure, with differences in frequency and intensity. Sound travels through the pinna of the ear into the auditory canal, which ends at the tympanic membrane, or eardrum (outer ear). Vibrations move the ossicles - the malleus, incus, then the stapes, which in turn moves the oval window membrane (middle ear). Pressure at this point is 20 times higher than the tympanic membrane by sound amplification from the ossicles (needed because waves move slow through aqueous environment. This membrane moves fluid in the cochlea (inner ear), which is divided into the fluid filled scala vestibule, scala media and scala tympani, separated by Reissner�s membrane, the tectorial membrane and the basilar membrane. The endolymph in the scala media is +80 mV higher than the perilymph in the other two chambers because of high K levels in the endolymph, and opposing high Na levels; this endocochlear potential enhances auditory transduction. Vibrations in the endolymph travel into the basilar membrane in waves; its distance is mediated by the frequency (lower travels farther). These vibrations travel into the organ of Corti, whose hair cells (the auditory receptor cells) with attached stereocilia vibrate and translate the vibrations into chemical signals by the forced increase of inward potassium current. As the cilia bend, potassium channels are opened, which then causes a depolarization. After that, voltage gated calcium channels are opened which can form synapses with neurons in the spiral ganglion. Axons from here then enter the auditory-vestibular nerve (cranial nerve 8) in the medulla before heading to the dorsal and ventral cochlear nucleus (which already has a tonotopic map). From there, all ascending auditory pathways project to the inferior colliculus (ventral nuclei axons use the superior olive as a go-between). Finally, it heads to the medial geniculate nucleus (MGN) in the thalamus. Information then proceeds to the primary auditory cortex, A1 or Brodmann�s area 41 in the temporal lobe. Most signals come from the single row of inner hair cells; the three row outer hair cells tend to act as a cochlear amplifier by their attachment to the tectorial membrane and amplify the response of the basilar membrane so the inner hair cells bend more.
Sound loudness is encoded by the firing rates of neurons and the number of active neurons. Neurons are usually responsive to one frequency. Frequency maps of the auditory structure are called a tonotopy (from which part of the basilar membrane is vibrating), and are useful at higher frequencies. Phase locking is the consistent firing of a cell at the same phase of a sound wave - from the frequency of neuron firings, one can determine the frequency of the sound. Sound localization is needed to: in the horizontal plane, the interaural intensity difference is important in ascertaining direction (the difference in intensity between what your left and right ears hear). Also interaural time delay helps, by using the time delay to obtain angle of sound direction. These two are part of the duplex theory of sound localization. Binaural neurons, that is, neurons influenced by collective sound from both ears, works on the principle that the interaural delays (time for axons to travel to the superior olive) will affect the intensity of summated EPSPs. However, localizing sound in the vertical plane isn�t much affected by the duplex theory; it can only be impaired by blocking or bypassing the pinna.
The vestibular system uses hair cells to transduce movements and maintain balance and equilibrium. All hair cells are located in interconnected chambers called the vestibular labyrinth, which contain the otolith organs, for detection of force of gravity and tilt of head, and the semicircular canals, which are sensitive to head rotation. The otolith organs, the saccule and utricule, are at the center and detect head angle and linear acceleration by the force on the otoliths (calcium carbonate stones) on the macula (the sensory epithelium). The saccular maculae are vertical; the utricular maculae are horizontal, and hair cells on both can cover all directions. This force works then on the cilia - when it pushes them toward the kinocilium (the big long hair), depolarizing EPSP�s occurs. The semicircular canals lie within 90 degrees of each other and sense angular acceleration. Their hair cells lie within the ampulla and project into the cupula in the same direction; they get all excited together. Endolymph fills the semicircular canals and moves very slowly (inertia) when the head is turned, thus exerting a force on the cupula, which bends the cilia and exciting or inhibiting transmitter release. The 3 canals sense all possible rotation angles. Axons project to cranial nerve 8, then to the vestibular nucleus, which either sends axons to the ventral posterior (VP) nucleus, or excites motor neurons through the vestibulospinal tract or the medial longitudinal fasciculus (legs; trunk and neck). The vestibule-ocular reflex (VOR) keeps your eyes pointed in one direction while you are moving wildly.
Part V: Somatic Sensory System (Touch, Pain and Temperature)
Touch begins at the skin (hairy or glabrous), made up of the epidermis and dermis, infiltrated with mechanoreceptors, which are sensitive to physical changes. Mechanoreceptors have unmyelinated axons with mechanosensitive ion channels whose gates depend on physical changes. Meissner�s corpuscles and Pacianian corpuscles (the largest) are rapidly adapting (stopping response quickly though stimulus continues), while Merkel�s disk and Ruffini�s endings are slowly adapting. Pacinian corpuscles and Ruffini�s endings have large receptive fields. Compression of the Pacinian corpuscle compresses the �capsule� and opens the channel, allowing depolarization, but with continued pressure, the capsule slips away on a viscous fluid and dissipates the potential. Hair grows from embedded follicles which, when bent, deforms the follicle and surrounding tissue. This can change the action potential or firing frequency. Fingertips are the most sensitive to mechanoreception. The skin is filled with primary afferent axons that enter the spinal cord through the dorsal roots with their cell bodies in the dorsal root ganglia. There are four types: A-alpha, the biggest (proprioceptors); A-beta, the second biggest (mechanoreceptors); A-gamma (for pain); and C, which is unmyelinated (temperature).
The spinal cord is divided up into 30 spinal segments, with 30 nerves between the notches in the vertebrae. The dermatome is the area of skin innervated by a single spinal segment. They are separated into cervical (1-8), thoracic (1-12), lumbar (1-5) and sacral (1-5). Sensation can be lost if more then three adjacent dorsal roots are cut, since there is overlap. The cauda equine are the spinal nerve bundles down the lumbar and sacral column, in a sac of dura filled with CSF. Lumbar puncture or spinal tap utilizes this sac. Inside the cord is an inner core of gray matter surrounded by white matter in columns, with dorsal horn, intermediate zone and ventral horn divisions. The trigeminal nerve (cranial nerve 5) serves the face and is made up of twin nerves that split into three covering the face, mouth, tongue and dura mater. Second-order sensory neurons receive sensory input from primary afferents; most of these lie in the dorsal horns.
The touch pathway is the dorsal column-medial lemniscal pathway. Ascending large axons enter the dorsal column and end at the dorsal column nuclei, where it hits the medulla. At this point they switch sides and ascend into the medial lemniscus (white matter) through the medulla, pons and midbrain into the ventral posterior (VP) nucleus of the thalamus. It ends up in the primary somatosensory cortex, or S1, which is very responsive to touch stimuli. Area 3b deals with texture, size and shape, and projects to 1 and 2. The posterior parietal cortex lies right in the back, which helps interpret spatial relationships, accurate body image and learning tasks with coordination of the body in space. A somatotopic map (homunculus) maps surface sensations onto the brain structure; these are discontinuous. Continuous remapping (plasticity) can affect amputees (phantom limb) or people who utilize a certain physical action often; the brain area can be reconfigured or enlarged. The posterior parietal cortex is concerned with movement planning, object recognition and attentiveness, leading to agnosia (no recognition) or neglect syndrome (an entire hemisphere is disregarded). Thermoreceptors sense temperature, and include warm and cold receptors.
Pain comes from the response to nocireceptors, small unmyelinated receptors that signal damage or damage risk. It can continue even after nocireceptor response leaves. Polymodal nocireceptors react to many stimuli - specifically, there are mechanical, thermal and chemical nocireceptors. Hyperalgesia is the reduced threshold of pain, or an increased intensity in pain stimuli, or even spontaneous pain. Bradykinin is a peptide that activates nocireceptor responses; prostaglandins can increase sensitivity to stimuli; and Substance P, made by the nocireceptors, causes vasodilation and release of histamine. The larger A-gamma fibers cause a fast, sharp first pain, and the smaller C fibers cause a dull second pain. The fibers first synapse in the dorsal horn and branch right away into the zone of Lissauer, which synapses on cells in the substantia gelatinosa, on the rim of the dorsal horn. The glutamate neurotransmitter stimulates Substance P release - but with chili, the capsaicin causes the release of Substance P. Capsaicin receptors are found in the dorsal root ganglions and have polymodal pain responses. Its calcium channels are activated by heat; they are also activated by extreme pH. Another related receptor in the DRG is activated by cold and menthol. Referred pain is when pain signals from the viscera cut across at the cross point and are mistaken for skin stimulation, localizing pain on the outside where there isn�t any.
Pain signals go up the spinothalamic pain pathway into the thalamus without synapsing during the path. The axons decussate immediately after leaving the ganglion; they are small and unmyelinated, as mentioned. Trigeminal information is relayed up the trigeminal pain pathway and first synapse in the spinal trigeminal nucleus of the brain stem. The axons cross and ascend to the thalamus in the trigeminal lemniscus.. Touch and pain are segregated up to this point.. The gate theory proposes that pain is regulated at the same time by mechanoreceptive axons that fire concurrently and activate interneurons that suppress the pain signals. Pain suppression is linked to the periventricular and periaqueductal gray matter (PAG), which can cause analgesia (absence of pain) by a control pathway that goes from the PAG to the medulla to the dorsal horn. Opioids can also be used to control pain; these are called endorphins in the human body.
Part VI: Movement
Muscles are smooth - involved in peristalsis and blood pressure control - and striated, where they are either cardiac or skeletal. Each skeletal muscle is enclosed in connective tissue that forms tendons, which connects to the bone. Each muscle is made of muscle fibers and each is innervated by one axon, and are collectively called the somatic motor system. Muscles can be antagonists, like the flexors and extensors, or synergists. Muscles responsible for the trunk are axial and those for shoulder, elbow and pelvis movement are proximal. The distal muscles are for the hands and feet. Somatic motor neurons in the ventral horn are called lower motor neurons, and stem from the spinal nerves. These include alpha and gamma motor neurons. Alpha motor neurons are responsible for generation of force; a motor unit is this neuron and the muscles it innervates. A motor neuron pool is the alpha neurons needed to innervate a single muscle. Acetylcholine is released at the neuromuscular junction to cause an EPSP large enough to trigger an AP. This causes a twitch - and many of these sums up and equals the contraction. Muscle concentration is also graded by recruiting additional synergistic motor units. The more, the better controlled the reaction is. Input comes from dorsal root ganglion cells that innervate an apparatus in the muscle, called the muscle spindle; upper motor neurons, which pass along EPSP and IPSPs; and interneurons in the spinal cord. Fast motor units contain rapidly tiring white fibers and slow motor units contain slowly tiring red fibers; these generate corresponding numbers of APs. Prolonged activity or inactivity can increase or decrease the growth of the fibers and motor units.
Excitation-contraction coupling: after an AP in an alpha neuron axon, Ach is released at the neuromuscular junction. Nicotinic receptor channels open and the postsynaptic sarcolemma (cell membrane of the muscle fiber) depolarizes. Cholinesterase terminates signal. Na channels open and an AP is generated down the fiber and sarcolemma, where it depolarizes the T tubules, which opens the calcium channels of the sarcoplasmic reticulum (like the ER). The calcium then binds to troponin, the protein covering the myosin attachment sites on the actin molecule. Those sites are exposed and then myosin heads are able to bind actin and rotate, �pulling� the muscle. This pulls the thin filaments along the thick filaments brings the muscle fibers together such that the sarcomere (the muscle myofibril between the Z lines) shortens. They disengage and cycle until ATP runs out. As the muscle relaxes, calcium is pumped back into the sarcoplasmic reticulum by ATP, and troponin covers the binding sites again. This causes ballistic movements: commands are given, and the muscle contracts.
Proprioreceptors detect body position and movement in space. These include muscle spindles (situated in parallel), and associated Ia axons, which detect changes in muscle length and innervate the extrafusal fibers of the muscle (which lie outside the spindle and make up most of the muscle). These are the thickest myelinated axons in the body and conduct action potentials very rapidly; they make up the monosynaptic myotatic reflex, because it involves muscle sensory feedback to help out in the reflex wherein a muscle being pulled pulls back. The Ia axons synaptically depolarizes the alpha motor neurons, which then causes the muscle to contract and shorten, decreasing Ia activity. Gamma motor neurons innervate the intrafusal fibers of the muscle spindle at each end. Contractions of these fibers pulls on the equatorial region, increasing Ia activity. Thus, a loop is created: gamma to intrafusal to Ia afferent to alpha to extrafusal. This keeps the muscle length the same by sensing deviations with Ia and compensating with the extrafusal fibers. The set point is changed by changing the activity of the gamma neurons at the beginning of the loop. These two types of neurons are stimulated simultaneously. Other proprioceptors include the Golgi tendon organ which monitors muscle tension or the force of contraction. These are situated in series and are innervated by Ib sensory axons, which branch in the spinal cord and synapse on interneurons in the ventral horn that mediate their action on alpha motor neurons. With the reverse myotatic reflex, they regulate muscle tension within an optimal range (to prevent overload) by inhibiting the alpha motor neurons to slow muscle contraction. As the tension falls, inhibition is lessened and contraction again increases. Interneurons also help out with reciprocal inhibition (to remove difficulty placed by your own antagonist muscles always opposing you) or the flexor reflex response that also requires extensor and flexor action on the other side of the leg.
The brain communicates with the motor neurons by the lateral and ventromedial pathways. The lateral pathway is involved in voluntary movement of the distal musculature and is under direct cortical control, and the ventromedial pathway is involved in posture and locomotion and is under brain stem control. The lateral pathway contains the corticospinal tract which originates in the neocortex and is one of the largest in the CNS, with a million axons. 66% originate in area 4 and 6 of the frontal lobe, called the motor cortex. The rest regulate the flow of somatosensory info to the brain. Axons go from the cortex to the internal capsule, to the telencephalon and thalamus, through the cerebral peduncle (bunch of axons in the midbrain) into the pons and then to the pyramidal tract at the base of the medulla, where decussation occurs. Motor activity is controlled by opposite sides. This pathway also contains the rubrospinal tract originating in the red nucleus of the midbrain. These immediately cross over in the pons and join the corticospinal tract. Large input comes from the region of the frontal cortex that affects the corticospinal tract. Lesions cause movement deficit that is recoverable.
The ventromedial pathway is made of four descending pathways. The vestibulospinal tract keeps the head balanced on the shoulders and originates in the vestibular nuclei of the medulla, which brings info from the vestibular labyrinth (fluid filled canals associated with the nuclei)to the inner ear. Fluid motion activates hair cells that signal these nuclei via cranial nerve 8. It controls neck and back muscles to guide head movement. The tectospinal tract starts in the superior colliculus which gets direct retinal input. It gets visual cortex projections and afferent with sound and touch info. It then constructs a map of the world that one can focus on. The pontine and medullary reticulospinal tracts arise from the reticular formation of the brain stem which runs in the brain stem through the core. The pontine tract helps resist gravity, while the medullary tract does the opposite.
The motor cortex lies behind the central sulcus. Brodmann�s area 4 is known as the primary motor cortex or M1. Brodmann�s area 6 is probably a specialized area for skilled voluntary movement, containing the premotor area (PMA) that eventually innervates proximal motor units, and supplementary motor area (SMA) that innervates distal motor units directly. SMA is heavily interconnected with M1. The posterior parietal cortex helps in decision making, and prefrontal cortex works with executive function. Motor decisions and feedback are passed through a loop involving the cortex, the thalamus and the basal ganglia. Cortical input from M1 and the prefrontal cortex excite the putamen of the basal ganglion (which, along with the caudate nucleus make up the striatum), which releases inhibition on the globus pallidus, which then releases its inhibition on VLo. VLo is the major info, or input, to the ventral lateral nucleus (VL) in the thalamus, which connects to the SMA. Increased inhibition leads to hypokinesia, a paucity of movement, most commonly seen as Parkinson�s disease. The organic basis is degeneration of substantia nigra inputs to the striatum. These inputs usually use dopamine to excite the putamen in the motor loop, but there is no activity with no dopamine, so dopa treatments are used to increase dopamine levels. Huntington�s disease exhibits hyperkinesias, usually from massive loss of neurons in the basal ganglia.
The cerebellum controls the timing of the sequence of muscle contractions, without which one would have ataxia. Disjointed movement is known as dyssynergia. Dysmetric patients cannot touch their nose. Te cerebellum is not split down the middle and is made up of a repeatedly folded piece of cortex. It contains ridges known as folia, and divided into 10 lobules by deep fissures. It contains around 50% of the neurons in the CNS. Neurons deposited deep in the white matter are called deep cerebellar nuclei, which relay most of the cortical output to the brain stem. There are two hemispheres separated by a vermis, which contributes to ventromedial pathways. The motor loops runs as follows: axons from layer V pyramidal cells in the sensorimotor cortex, from frontal areas 4 and 6, the somatosensory areas and the posterior parietal areas form a large projection to the pontine nuclei in the pons - this is about 20 million axons, 20 times more than the corticospinal tract. The lateral cerebellum projects back to the motor cortex via the ventral lateral nucleus (VLc) of the thalamus. Purkinje cells are the only output cells; the other cells inhibit the Purkinje cells. This structure is set up for learning. Practice does make perfect, as synapses are strengthened through practice.
Part VII: Vision
Light is visible electromagnetic radiation that has certain wavelength, frequency and amplitude. Hot colors have longer wavelengths and less energy than cool colors; of course, these are only "colored" by the brain. These waves of electromagnetic radiation move as rays, which are studied using optics. Reflection is the bouncing of light rays off a surface; absorption is the transfer of light energy to a surface; and images are made through refraction, which is the bending of light rays from one transparent medium to another.
The pupil allows light to enter the retina and is surrounded by the colored iris, which in turn is covered by the glassy corneal surface. It is nourished by the aqueous humor. The cornea is continuous with the hard white sclera which is attached to the conjunctiva, a membrane that covers the extraocular muscles that move the eyeball. The optic nerve carries the axons from the retina to the brain at the base. Behind the iris is the lens, which focuses the light onto the retina. It is held in place by the ciliary muscles, which are attached to the sclera. Adjustment of these muscles (called accommodation) changes lens shape and adjusts focus. Inside the eye are the aqueous humor and the vitreous humor which fills the space between the lens and retina; it is jellylike and maintains eye shape. Within the retina is the macula, the middle dark yellow region that has no large blood vessels and had improved vision quality. The fovea is the dark spot in the center of the macula that serves as a reference point (nasal - nose, temporal - temple, superior - above, inferior - below) and is specialized for high resolution vision by the concentration of photoreceptors (all cones; cell layers pushed aside so direct photoreceptor contact). At the fovea, there are no other cell layers, and the macula acts as a funnel to the direct photoreceptor layer in the fovea. The optic disk at the back is the optic nerve head, and is the blind spot. The cornea bends light on its curved surface into the aqueous humor to the retina; the focal distance is the distance from the curve point to the convergence point. The reciprocal of this is the diopter, used in opthalmology. The pupils can also contract, like the lens, to increase the depth of focus. This pupillary light reflex (adjustment to light levels) involves a synapse from the brain to the motor neurons of the eye. The visual field is what one can see at one given time. Objects can be discerned by visual acuity (differentiation of two nearby points) and visual angle.
Visual info is processed by the photoreceptors (the only light sensitive retinal cells), including the 125 million rods, which are filled with disks and are useful for night vision, and the 7 million cones, which are shorter and used for day time vision. Rods are most sensitive to green and are insensitive to red; they are also more sensitive to light. This cell layer is on the outside embedded in an epithelium that absorbs light that could blur an image. Rod phototransduction goes as follows. In the dark, a dark current is initialized by the steady influx of sodium, heightening the rest potential to -30 mV (a depolarization). These channels are gated by cGMP second messenger and are produced in the photoreceptor by guanylate cyclase; light reduces cGMP and hyperpolarize the cell. It does this by changing the conformation of retinal (from cis to trans), a prebound agonist on the pigment rhodopsin. Retinal activates opsin which causes bleaching - the wavelengths absorbed by rhodopsin change. This stimulates the G-protein transducin which activates phosphodiesterase, which breaks down the cGMP. This pathway is capable of signal amplification, so a little light can go a long way. Prolonged light causes saturation and hyperpolarization will stop (in bright daylight), so the cones take over, after 10 minutes of light adaptation. The potential drops to -60 mV and less neurotransmitter is released. The process is the same, but the rhodopsin is now iodopsin and the opsins are different, and have different spectral sensitivites - "blue", 430 nm; "green", 530 nm; and "red", 560 nm (short, medium and long). According to the Young-Helmholtz trichromacy theory, color is assigned by a comparison of info from the three types - but there is no red cone, and sensitivities can overlap. The other color theory is the Hering opponent process hypothesis, which predicts 2 opposing pairs of detectors (R, G, B and Yellow), but there are only 3 cones and 3 photopigment genes. The transition back to rod vision takes 20 minutes and is called dark adaptation. The pupils then dilate, unbleached rhodopsin is generated and the transition back to mostly rods done.
Further in, potentials travel through the outer nuclear layer and the outer plexiform layer to the inner nuclear layer, where glutamate channel/receptors (photoreceptors make the glutamate) pass on potentials to the bipolar cells (horizontal cells modulate info from photoreceptors to bipolar cells); and then to the amacrine cells, where they are finally projected to ganglion cells and other predecessors in the pathway. In OFF bipolar cells, glutamate-gated cation channels mediate depolarizing EPSPs from glutamate gated sodium channels (no light, more glutamate); ON bipolar cells respond to glutamate by hyperpolarizing using G-protein coupled receptors (light on, less glutamate). Each cell gets input from a cluster of photoreceptors, containing from 1 to thousands. Its receptive field is the retinal area that changes the cell membrane potential upon light stimulation - it is made up of the receptive field center and the receptive field surround, with antagonistic responses for each section (if ON in one, OFF in the other). The ganglion cell is the only retinal output, and propagates action potentials down the optic nerve to the brain (the other cells respond with graded potentials). There are ON and OFF ganglion cells too, stimulated by light and dark in their receptive centers respectively. Like bipolar cells, their response to light in the surround is different from their response to light. These center and surround areas are fed info by the horizontal cells and help create peripheral vision. Cell types include M-type, P-type ganglion cells and various nonM-nonP ganglion cells. M-types have large receptive fields, are more sensitive to low-contrast stimuli and fire quick APs. P-types make up most of the ganglion cells, are small, and used for fine detail. There are color sensitive neurons known as color-opponent cells, which have wavelengths that cancel when each are shown in the center and surround respectively. In P cells, it is red and green, and in nonM-nonP cells, it is blue and yellow.
The retinofugal projection is the neural pathway that continues from the optic nerve to the brain. It starts the optic nerves, which exit each eye from the optic disks and combine into the optic chiasm at the base of the brain. Axons from the nasal retinas (left side of right eye, right side of left eye) cross from one side to the other at this point (decussation). Each side sees one visual hemifield, and the central portion visible to both is the binocular visual field - each hemifield is "visible" by the other side. After that, the axons form the optic tract. Cutting of a nerves would blind one eye, but severing the tract would cut off an entire hemifield. From here, some axons go to the hypothalamus, 10% innervate the superior colliculus in the midbrain through the thalamus (retinotectal projection), and the majority go to the lateral geniculate nucleus (LGN) of the dorsal thalamus, where axons are projected to the primary visual cortex or Brodmann's area 17 or V1 or striate cortex (optic radiation). Cranial nerves involved include the optic nerve, oculomotor nerve, trochlear nerve and the abducens nerve. A retinotopy is a 2D map of the retinal surface projected onto the superior colliculus; it is used to help orient the eyes in response to new stimuli.
The LGN is split into 6 layers, the inner two of which are called the magnocellular layers and process M-cell info. The other 4 layers are called the parvocellular layers and process P-cell info. The koniocellular layers lie ventral to all the layers and receive input from the nonP-nonM ganglion cells. Temporal retinal axons (ipsilateral) synapse layers 2, 3 and 5. Nasal retinal axons (contralateral) synapse layers 1, 4 and 6. Color opponency is exhibited in the koniocellular areas of layer 3 and 4. Primary input then goes to the visual cortex, but secondary input is at the arousal centers. The primary visual cortex is made up of a thousand cortical modules, and exists in 9 layers, the first of which is devoid of neurons; these are I-IV (A-C[alpha and beta]), V and VI. Layer IV is the thickest. Magnocellular layers travel to layer IVCalpha (which possesses orientation selectivity, best response to thin slit of dark or light) before going to IVB; parvocellular layers travel to layer IVCbeta (which has direction selectivity) before going on to the blobs in layers II and III, and then to the interblobs. Blobs indicate segregation of the M and P channels and does object color analysis (continued parallel processing); bivisual synapses finally occur in the interblobs.
Two major streams occur in 24 cortical areas. These include the ventral and dorsal streams. The ventral stream uses V1-V4 and IT (inferior temporal lobe), which does concentric circles, object and face recognition. The dorsal stream uses V1-V3, MT (medial temporal lobe), and MST, and does motion processing, and it projects to the areas for eye movements.
Part VIII: Chemical Control of Brain and Behavior
The secretory hypothalamus, connected to the pituitary gland just below, secretes its hormones directly into the blood and integrates somatic and visceral responses in accordance with needs of the brain. Lesions can disrupt bodily functions. It controls homeostasis by maintaining the internal environment. It is broken into the lateral, medial and periventricular zones; this latter zone lies close to the third ventricle. The cells within include the suprachiasmatic nucleus, which synchronizes circadian rhythms; cells that control the ANS (including those in the nucleus of the solitary tract, connected to the hypothalamus); and the neurosecretory neurons, which extends axons into the pituitary gland. The pituitary itself has a posterior and anterior lobe, controlled in different ways. Magnocellular neurosecretory cells control the posterior pituitary by releasing neurohormones directly into that section, including oxytocin, involved in childbirth and ejection of milk, and vasopressin or ADH, which regulates blood volume and salt concentration. Their release is stimulated by some sensory stimulus, or hormonal feedback from the kidneys, respectively. Parvocellular neurosecretory cells secrete their hypophysiotropic hormones into the bloodstream by the third ventricle, where it then goes to the anterior pituitary - through the hypothalamo-pituitary portal circulation. These releasing hormones entice the anterior lobe to make and release hormones acting on the gonads, thyroid, mammary and adrenal glands, including follicle stimulating hormone; luteinizing hormone; thyrotropin, corticotropin, growth hormone and prolactin. These hormones are active in reproduction, metabolism and growth.
The periventricular zone also controls the ANS. Its motor neurons are instructed by the preganglionic neurons of the spine and brain stem, which innervate the postganglionic neurons, which collectively are called the autonomic ganglia. The sympathetic divisions, which control the four F�s (fight, flight, fright and fuck), are innervated by axons in the intermediolateral gray matter of the spine, which go through the ventral roots and emerge from the thoracic and lumbar segments where they synapse abdominal ganglia or ganglia of the sympathetic chain. The parasympathetic divisions, which controls digestion, growth, immune response and energy storage, are innervated by axons from the brain stem and sacral spine which travel through cranial and sacral nerves, and usually travel very far, as their ganglia are close to their target organs. Together, the ANS innervates glands, smooth muscle and cardiac muscle tissue. The enteric division is like a little brain because it is in the lining of the digestive system and basically operates independently in controlling the passage of food from oral to anal openings. Preganglionic neurons release acetylcholine to both divisions, which opens Ach-gated channels and evokes fast EPSPs in neuromuscular junctions and slow EPSPs in the ganglia. Other proteins are also released which have modulatory action. Postganglionic neurons release Ach to the parasympathetic division and norepinephrine to the sympathetic division. Neurotransmitters and drugs innervating either side are either sympathomimetic or parasympathomimetic.
The diffuse modulatory system controls diffuse regulatory functions. They are made of a small set of neurons usually in the brain stem, with up to 100,000 postsynaptic neurons in contact with it. The ventrolateral preoptic areas include all the following arousal centers; stimulation of these areas induce sleep. The two noradrenergic locus coeruleus in the pons utilizes NE and innervates all areas of the brain, to help out in the regulation of attention, arousal, sleep, learning, memory, anxiety, pain, mood and metabolism. The nine serotonergic raphe nuclei all contain serotonin and lie to the side of the midline of the brain stem. This also projects to most levels of the brain, and with the locus coeruleus, are part of the ascending reticular activating system, which arouses the forebrain. It is involved in sleep, mood and emotional behavior. The dopaminergic substantia nigra and ventral tegmental area both contain dopamine and are involved in voluntary movement and reward systems for adaptive behaviors, using the mesocorticolimbic dopamine system. Acetylcholine is utilized in the basal forebrain complex and the pontomesencephalotegmental complex, which innervates the hippocampus, neocortex and dorsal thalamus to regulate excitability of sensory relay nuclei and cycle-involved nuclei. Psychoactive drugs, hallucinogens and stimulants all can work on the modulatory system.
Part IX: Sleep and Circadian Rhythms
Sleep is a readily reversible state of reduced responsiveness to and interaction with the environment, unlike comas and anesthesias. One can be in rapid eye movement or REM sleep or non-REM sleep. Non-REM sleep (75% of the time) is more for rest and a revisiting of what they did during the day, because of lessened muscle tension and some movement, usually for position adjustment. REM sleep (25%) has, in contrast, an active, hallucinating brain in a paralyzed body. This paralysis is called atonia, with almost total incapability of moving, except for a little respiration and the eye movement and inner ear muscles. Core temperature lowers, heart rates increase and sexual organs get erect for non-sexual reason. Electroencephalograms, or EEGs, charts cortical synaptic activity/ dendritic current (basically presence of thought) and tends to show wide difference in brain activity within these two types of sleep. We go through cycles called ultradian rhythms - generated by the thalamus - which last 90 minutes and encompass going through the 4 stages of non-REM sleep into REM sleep and back. Stage 1 is transitional and short, and we are easily wakened; synchronous theta rhythms occur (4-7 Hz). Also occurring are slow alpha rhythms (awake but sleepy - 9-13 Hz) and higher frequency but lower amplitude asynchronous beta rhythms (awake and alert, >14 Hz) that disappear as we fall into non-REM sleep and reappear during REM sleep, when our brain state is similar to being awake. Greater synchronization causes greater amplitude, or greater firing. Stage 2 is deeper, eye movements cease and it extends15 minutes; the K complex (high-amplitude sharp wave) and sleep spindle (made by the thalamic pacemaker) occur. Stage 3, also 15 minutes, has slower synchronous delta rhythms (<4 Hz) and eye and body movements are absent. Stage 4 is the deepest stage with large delta rhythms, for 20 to 40 minutes. Afterwards, it goes into stage 2 for a little and then progresses to a brief REM sleep (desynchronized EEG). As the night goes on, stages 3 and 4 get shorter and the REM periods get longer, up to around 50 minutes.
Reasons for sleep include restoration or adaptation. Adaptationists believe that sleep is enforced isolation time for hiding, conservation of energy purposes, restoration of tissue and immune cells, and the release of groth hormone during adolescence. REM seems to be for learning and integration/consolidation of memory, as its deprivation tends to worsen our learning ability. However, depriving non-REM sleep does the opposite. Dreams are apparently associations of the cerebral cortex stimulated by discharge of the pons through the pontine neurons into the thalamus and into the cortex; extrastriate cortex activity is high. Wakefulness is promoted by the neurons of the ascending reticular activating system that contain NE and serotonin, the Ach-containing cells of the brain stem and basal forebrain, and the histamine-containing cells of the midbrain. All these cells synapse the thalamus, cortex and other regions, resulting in depolarization and excitability. Falling asleep and non-REM sleep includes a decrease in the firing of NE and Ach modulatory neurons. However, some cholinergic neurons in the basal forebrain increase firing. Inter-thalamus and thalamus to cortex connections seems to coordinate activity during spindle and delta rhythms (which feature much more negative membrane potentials). During REM, motor cortex firings are blocked (this is adaptive, because of possible injury to self), as are sensory info flow to the cortex, mainly by the rhythmic behaviors of the thalamus. The reticular activating system stops activity but Ach neurons in the pons increase in activity. Sleep apparently is promoted by muramyl peptides of bacterial origin, which promote fever and stimulate the immune system; IL-1, made by the brain, also stimulates the immune system; and adenosine, which inhibits Ach, NE and 5-HT (serotonin) modulatory systems and whose receptors caffeine blocks. Activity of the awake brain increases adenosine levels - which also indicates the depletion of energy by neurons - and thus inhibits modulatory systems associated with being awake, making it more likely one will fall asleep. These levels fall during sleep. Mitochondrial genes and genes coding for transcription factors seem to also play a role in promoting sleep. Disorders include insomnia, sleepwalking, sleep apnea, sleep state misperception (where one dreams that they can't sleep) and narcolepsy, where one progresses from being awake to REM sleep without a transition.
Circadian rhythms, the cycles of light and dark, play a part in regulation of behavior - including body temp, blood flow, urine production, hormone levels, hair growth and metabolic rate. So-called clocks in the body are biological, in the brain, and can run similarly even if the cycles are stopped. Occasionally, it will need to reset and thus looks to external stimuli. Environmental time cues are known as zeitgebers and their deprivation leads to a 25 hour rhythm; however, as time passes, they begin to run 36 hour rhythms, staying awake for 20 hours and sleeping the rest of the time. Some physiological measures run on a consistent schedule and not different, under influence of zeitgebers, and thus are probably run by a different clock. In the brain, the biological clock that produces circadian rhythms is known as the suprachiasmatic nuclei (where each neuron is a clock), which lies bordering the third ventricle. Stimulation leads to shifts in rhythms, but lesions do not stop rhythms. The retinohypothalamic tract coordinates light input; retinal axons synapse SCN neurons, which use GABA as their primary NT. Their receptive fields are nonselective and contain no rods or cones - these receptors are believed to be the cryptochrome protein. Output from the SCN goes to the hypothalamus and then to the pineal gland, but also to the midbrain and diencephalons. Their rhythmic messages, on the 24-hour cycle (with high activity in the day and low activity at night), are communicated using efferent axons with action potentials, but these potentials are not necessary. So how does it work? Possibly by gene expression through a negative feedback loop. Mutations in the period and timeless genes cause changes in the cycles, longer or shorter or just random periods. These photosensitive genes build up mRNA that produce the tim and per protein until production ceases, whereby the degradation of the protein by light leads to an increase in production. The whole SCN process, and inter-SCN communication, is not well understood. Pathway: sensory info to SCN clock to brain processing to motor neurons and behavior. Other pathways include ultraradian cycles (less than a day, for breathing and eathing), infraradian cycles (many days, for the reproductive cycle), and circannula cycles (once a year, for mating and migratory behavior).
Part X: Sex and Gender
Sex is determined genetically through the X and Y chromosomes: XY for normal males and XX for normal females. The X chromosome is significantly larger than the Y, and a mutation in the X is detrimental to the male, who has only one copy of the X gene. These mutations lead to many X-linked diseases such as hemophilia, color blindness and muscular dystrophy. Sexual differentiation is started by the presence of the sex-determining region of the Y chromosome (the SRY), which is located on the short arm of the Y chromosome and encodes for the testis-determining factor (TDF), which binds SF1 and other related proteins. The presence of the SRY and the Y gene determines maleness; thus, XXY, XYY and XXYY are all males. XXY males have Klinefelter's syndrome, and XYY males are known as "supermales", who are taller and have lower IQ than normal. YO males are all dead, and XO females have Turner�s Syndrome. The SRY and TDF allow development of the indifferent gonads into testes which can then make testosterone and Mullerian inhibiting factor/hormone (MIF or AMH). Testosterone allows the Wolffian duct to develop into the male internal reproductive system while MIF stops growth of the Mullerian duct. In females, the SRY is not there to release the hormone, and thus the Mullerian duct can develop into the fallopian tubes and the uterus while the Wolffian duct regresses. After 7-10 weeks, the difference in the external genitalia begins to show.
Sexual reproduction is a motivated behavior that has been favored by evolution possibly because of its possible diversity, the different offspring possible and the protection afforded by heterogeneity. Generally, one gamete is larger than the other resulting in a disparity in parental contributions. Also, parental investment differs, with a utilization of two strategies by one or both parents: 1) investing a lot in each offspring leads to greater likelihood of survival, and 2) investing a little in each leads to many, statistically increasing the chances that some will survive.
Sex response cycles include full participation of the mechanoreceptors in the external genitals and subsequent modulation of ANS activity. Mechanoreceptor axons, after arousal and stimulation, feed into the dorsal roots and columns and extend up into the parasympathetic neurons of the ANS, where they control engorgement and erection. They release a combination of ACh, nitric oxide and vasoactive intestinal polypeptide (VIP) into the erectile tissues, where they relax the muscles and allow blood to fill the organs. In the male, the hardness is caused by the spongy inner tissues expanding against the outer coverings of connective tissue to its max stretch. Other parasympathetic activity releases lubricating fluids for the plateau phase of sex. Orgasm and resolution are supported by the sympathetic neurons. The efferent axons trigger emission by contracting the muscles, allowing sperm to be propeled through the system to be combined with fluids before coordinated muscular contractions allow ejaculation. In females, the axons stimulate strong muscular contractions. Resolution takes much longer in males. Orgasms in women are more variable in frequency and intensity. The actual mechanisms of climax are yet unknown. Neural pathways for other reproductive behaviors are also not known, such as female selectiveness, male promiscuity, differential mating systems and mental processing of advantages.
Sexual dimorphisms mark differences between male and female brain structures. Body size and shape differ, and thus their somatosensory and motor maps must differ as well. As well, the different physical organs - the testes, the breasts, the uterus and the others - require different mapping and bodily control. Sexual behaviors also require different brain functions. It is hard to match dimorphic neural structures to their function, however. The bulbocavernosus (BC) muscles are used to control penile erection and urine release in males and vaginal movements in the female; the muscles and assorted neuron pools are larger and more populated in males than in females. Another example includes the preoptic area of the anterior hypothalamus (POA), which has some role in reproductive behavior. Lesions reduce copulation and stop the estrous cycles. Within it, the sexually dimorphic nucleus (SDN-POA) is 3 times bigger in the male, and some of the interstitial nuclei of the anterior hypothalamus (INAH) are double the size in males. In castrated males, the SDN-POA are the same size as in females; if testosterone is given to newborn females, the SDN-POA enlarges to male size. However, destroying the SDN-POA has little effect on male sexual behaviors. Findings recently show that INAH-3 is the same size in women as it is in homosexual men, which promote a biological reason for being gay. A genetic basis, within the X chromosome, has been proposed. Men are also said to perform better in visualization and mathematical reasoning, while women are better at verbal tasks. However, some of these may be explained away by child/adult experience, which can be modified. As well, the size of the corpus callosum seems to be slightly different in both sexes.
The main male and female hormones are testosterone, an androgen; estradiol, an estrogen; and progesterone, a progestin. Testosterone in males is necessary for development of the male reproductive system and sperm maturation, and must be applied at birth or there will be no physical changes. Castrated males show lordosis (due to effects of estrogen and progesterone) but testosterone injected males exhibit mounting. Studies have shown that exposure of testosterone to female babies also promotes masculinization, which is irreversible. If those babies are given estradiol as adults, they don't turn back. This is a great example of an organizational hormone, which permanently rearranges brain chemistry. Its precursors are cholesterol and progesterone, and it can be directly converted to estradiol by aromatase. The estradiol then binds to receptors in the brain and promotes masculatory effects. In females, the alpha fetal protein blocks the estradiol from ever entering the brain. Estradiol, unlike testosterone, is activational, which means it has transient effects and must be periodically recirculated. Castrated males who are given estradiol as adults turn feminine. In females, estradiol promotes positive feedback to cause ovulation. However, heterosexuals and homosexuals of the same sex don�t have a difference in testosterone or estradiol levels. Other sex hormones include luteinizing hormone (LH) and follicle stimulating hormone (FSH), both gonadotropins, are secreted when gonadotropic releasing hormones (GnRH) from the hypothalamus stimulate the anterior pituitary. This is known as the hypothalamic-pituitary-gonadal axis (HPG). LH stimulates the testes to produce testosterone; FSH is involved with sperm maturation; and both play a large role in the menstrual cycle, where they increase the number of follicles, the cavities caging the eggs. Follicular secretions then inhibit growth of FSH and LH until hypothalamus feedback promotes strong LH release, which stimulates ovulation.
Hormonal defects include congenital adrenal hyperplasia, which is a defect in the enzyme that produces cortisol. There is no negative feedback, and there are extra androgens around that are not being converted into cortisol. This causes early appearance of male characteristics, increasing genital size for the males and introducing partially masculine genitalia for females. Probably by persuasion, CAH girls are likely to call themselves more tomboyish and tend to be more homosexual than normal women. Some males experience androgen insensitivity, where AMH and testosterone are still made by the testes, but androgen receptors don't work - therefore, no further masculinization. They have testes, but also a clitoris, a vagina, a labia and breasts; however, they are infertile and don't menstruate. They tend to adopt female sexual behaviors. In normal amounts, 5-alpha reductase causes testosterone (required for masculinization at puberty) to be converted to DHT, which causes stronger effects on androgen receptors. Inadequate amounts make genetically male boys seem female until puberty.
Part XI: Goal-Oriented Behaviors and Homeostasis
Functional units combine in hierarchical fashion to provide modes of goal-oriented behavior. These include reflexes, which operate in a stimulus-response relationship and either mutually facilitate or reciprocally inhibit each other. In induction, stimulus of either a flank or tail will allow both a tail deflection and an arch of the back muscles; the stimulation of one area lowers the excitement threshold on the other os it is more easily excited in future. Both precurrent inhibition and recurrent inhibition offer stimulation of a motor neuron and an inhibition, by differing mechanisms. In precurrent inhibition, the stimulation of a sensory neuron in one reflex pathway can both stimulate the motor neuron and an interneuron that will inhibit the motor neuron of the other pathway. Recurrent inhibition has stimulation of a reflex pathway that leads to stimulation of the motor neuron which then also stimulates an interneuron which inhibits the motor neuron of the opposing pathway. At the same time, the other pathway's inhibition of the former is released. Taxis are also functional units; these include geotaxis, phototaxis, heliotaxis, chemotaxis and teliotaxis, in positive and negative directions (towards and away from). Oscillations are the endogenous patterns of neural activity that can be entrained by sensory events. For example the cockroach lifts an upper right leg and a lower left leg at the same time, and a lower right leg and an upper right leg at the same time. Nervous activity controlling this is coordinated in order to walk.
Feeding in the blowfly is a good illustration of goal-oriented behaviors. Within its appetitive phase, the circadian oscillators run its active flying period; this is followed by geotaxis and chemotaxic orientation as directed by its antennae. Walking is then initiated until chemosensory hairs on the foot encounter food. The chemosensory hairs are most sensitive to sweet tastes, but it is sensitive to wetness (usually sweetness) and negatively toward salt; these signals can summate in space and time. The consummatory phase has a chain of reflexes that allow the rotation and positioning of the proboscis, starting peristalsis and filling of the guts and crop. These phases are potentiated by hunger. The satiation phase allows bouts to let chemosensory adaptation occur, which lets the action potentials decrease (receptor desensitization) until they stop and inhibition signals can be transmitted. These satiation signals occur because of the foregut stretch (precurrent inhibition). However, this is not the end of the meal, because the process is not affected by actual nutrition needs and it is not long enough. This is a short-term satiation and regulation of meal size by the foregut; long-term satiation and meal frequency is controlled by the crop, which periodically regurgitates food to the gut when the blowfly is hungry. Lesions on the ventral nerve in the crop increases meal frequency. Oppositely, if the recurrent nerve in the foregut is cut, there is no stretch satiation signal and the blowfly can eat until it explodes.
The hypothalamic regulation of homeostasis has three components: the humoral response (release of pituitary hormones); the visceromotor response (hypothalamic neurons adjust ANS in response to sensory signals); and the somatic motor response (hypothalamic neurons incite somatic motor behavior in response to sensory signals). These somatic responses are motivated behaviors, incited by the activity of the lateral hypothalamus. Usually, feeding behaviors are controlled by the lateral hypothalamus. This was tested by Randy Gallostel, who implanted electrodes in mice lateral hypothalami, which, when stimulated, moved the mouse to eat. During the training period, the mouse is taught to associate a motor response with a stimulus - in this case, pressing a bar when a light is on to get food - and, by posttraining, it only eats when hungry and when the bar is pressed when the lights are on. Lateral hypothalamic stimulation no longer moves the mouse to eat.
Homeostasis can be described by Bernard's Theory, which says that the internal environment stays constant; Richter's Theory, which says that behavior adds to the maintenance of homeostasis; and the Stellar model, which shows that the hypothalamus contains inhibitory and excitatory circuits leading to the activity of effectors that relate the state of various physiological variables to the complex behaviors constructed by the thalamus and cortex. Effectors include hormonal secretions, nervous system responses and other motivated behaviors. Interoceptive mechanisms monitor the physiological state and produce error signals from a set point that engages effector response according to strength of the error signal.
Osmometric thirst is the motivation to drink when dehydrated. This happens when water leaves the cell in times of hypertonicity; intracellular fluid contains 67% of the water, potassium and phosphates, and the extracellular fluid has the rest of the water and high salt. Osmoreceptors exist in the vascular organ of the lamina terminalis (OVLT), which changes action potential firing frequency due to loss of water in the blood. It can do this because there is almost no blood-brain barrier. When lesions are given to the OVLT, there are no responses to dehydration. In one model, the OVLT neurons directly excite the magnocellular neurosecretory cells to release vasopressin or ADH, which acts on the kidneys to increase water retention and inhibit urine production. In another model, OVLT neurons are surrounded by the mechanosensitive dendritic arbors of tonically active GABAeric neurons. These cells tonically inhibit the magnocellular neurosecretory cells of the lateral hypothalamus. When OVLT cells change shape due to dehydration, the GABAergic cells mechanically sense this and respond with reduced firing thus removing the tonic inhibition and activating the magnocellular neurosecretory cells that release vasopressin. Loss of vasopressin neurons is called diabetes insipidus, characterized by extreme thirst and frequent excretion of pale, watery urine.
Volumetric thirst, spurred by hypovolemia (decrease in extracellular fluid / blood volume), is induced after blood volume lowers and baroreceptors signal the change to the brain. The kidneys then produce renin, which breaks down angiotensinogen to angiotensin I, which is converted by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II directly causes vasoconstriction, but also goes to the subfornical organ in the telencephalon, which has a poor blood-brain barrier. Cells then project to the magnocellular neurosecretory cells of the hypothalamus to release vasopressin, and to the lateral hypothalamus, to elicit thirst behavior. Signals from the baroreceptors can also go through the vagus nerve and the nucleus of the solitary tract before stimulating vasopressin release. Angiotensin II works in the adrenal cortex to produce aldosterone, a steroid hormone which changes gene expression to sensitize the brain to angiotensin II and thus increase salt appetite to preserve electrolytes.
Anabolism, or anabolic metabolism, is the assembly of energy storage molecules like glycogen. During the postabsorptive state, catabolism, or catabolic metabolism, occurs by breaking down the stored glycerides into glucose, fatty acids and ketones. The system is in balance if intake equals outtake; otherwise, adiposity can increase to obesity, or it can decrease, resulting in starvation. The lipostatic hypothesis contains the idea that the brain monitors body fat and acts to defend this energy by regulating feeding behaviors. This hypothesis was supported by the later finding of the ob gene which encodes for the hormone that tells the brain that fat reserves are normal; this hormone was later found to be leptin, which is released by adipocytes and regulates body mass by acting directly on neurons of the hypothalamus. On the hypothalamus, it was found that lesions on the lateral side cause lateral hypothalamic syndrome or anorexia, and lesions on the ventromedial side cause ventromedial hypothalamic syndrome or obesity. Hypothalamic control is not based on this dual center concept, though.
When leptin is released in large levels into the bloodstream, they activate receptors on neurons of the arcuate nucleus of the hypothalamus, near the base of the third ventricle. The arcuate nucleus possesses two populations of cells wiht leptin receptors. The first population, the orexigenic peptides (because they increase appetite), is made of neuropeptide Y (NPY) and agouti-related peptide (AGRP) cells, which respond to a decrease in leptin. Variously, they project to the lateral hypothalamus to stimulate feeding; to the paraventricular nuclei to inhibit secretion of hypophysiotropic hormones which control ACTH and TSH production (which reduces energy expenditure by lowering cellular metabolic rate); and an increase in leptin reverses these effects. The second population, the anorectic peptides (because they diminish appetite), is made of alpha melanocyte stimulating hormone (alpha-MSH) and cocaine and amphetamine regulated transcript (CART), which project to the lateral hypothalamus to inhibit feedin; to the paraventricular nuclei to stimulate ACTH and thyrotropin release from the anterior pituitary; to activate the sympathetic ANS (which combined, allows energy expenditure, by raising cellular metabolic rate); and a decrease in leptin reverses these effects. AgRP and alpha-MSH are directly antagonistic, as they bind to the same MC4 receptor: alpha-MSH is the agonist, and AgRP is the natural antagonist that blocks alpha-MSH stimulation.
The nuclei and axons in the lateral hypothalamic area somehow motivate us to eat. Two important hormones in this are contribute to feeding behaviors, melanin-concentrating hormone (MCH) and orexin. MCH innervates most of the cerebral cortex, which organizes and initiates goal-oriented behaviors like searching the fridge. MCH is placed such that it can inform the cortex of leptin levels; also, injection of MCH stimulates feeding behavior, as does orexin. When leptin levels fall, MCH and orexin levels rise in the brain.
During the eating and prandial period (digesting), satiety signal determine the drive to eat. When the meal is over, these also inhibit feeding for a time afterward. Before a meal, the cephalic phase typically triggers physiological processes that anticipate breakfast, through saliva secretion and preparation of gastric juices. The gastric phase sees intensification of these responses through the actual eating, and the substrate phase contains the beginnings of nutrient absorption. The end of this meal is stimulated by gastric distension, cholecystokinin and insulin. Mechanosensory axons in the stomach sense stretching of the stomach walls, and signals extend up into the vagus nerve, where the axons activate neurons of the nucleus of the solitary tract in the medulla, inhibiting feeding behavior. This nucleus also takes in direct sensory input from the tastebuds and controls part of the ANS; this is how we can put off satiety when we are eating food that is tasty enough. Cholecystokinin is a peptide present in certain neurons in the CNS, the intestinal lining and in the enteric nervous system, and is released after stimulation of the intestines by certain foods, especially fatty ones. CCK works on the vagal sensory axons together with gastric distension to inhibit feeding behavior. Insulin is released by the beta cells of the pancreas, and is required for glucose transport into the other cells of the body. Glucose levels are tightly regulated by insulin; they rise when insulin levels lower, and they fall when insulin levels heighten. In the cephalic phase, parasympathetic innervation of the pancreas by the vagus nerve stimulates insulin release, which prompts a drop in blood glucose levels. This is detected by the brain, which increase the drive to eat. During the gastric phase, insulin is stimulated further by hormones like CCK; in the substrate phase, insulin release is maximal, but blood glucose levels start to rise. This dual rise is a satiety signal that tells the body to stop eating.
People eat because of hedonic motives (liking) or for drive reduction (remove hungriness). Electrical stimulation of the lateral hypothalamus stimulates feeding behavior; it also activates the dopaminergic neurons of the mesocorticolimbic dopamine system, which also plays a large role in motivating behaviors. It was believed that this projection served hedonic reward but destruction of the projection did not seem to reduce pleasure at eating � it only reduced motivation to seek food. Serotonin is another neurotransmitter involved with mood and food. Levels are low during the postabsorptive period, but rise steadily in anticipation of a meal and during the meal. Carbohydrates tend to cause large rises in serotonin levels, as a rise in carbohydrates also causes a rise in tryptophan, which serotonin is derived from. Drugs that elevate brain serotonin levels are good appetite suppressants; thus, Prozac can also cure bulimia nervosa, a disease caused by abnormalities in serotonin regulation.
Temperature homeostasis is controlled by neurons in the anterior hypothalamus. Changes in blood temperature are transduced into changes in firing rate. Humoral and visceromotor responses are initiated by neurons in the medial preoptic area of the hypothalamus, and somatic responses are initiated in the lateral hypothalamic area. When it gets cooler, the anterior hypothalamus detects this and stimulates TSH release from the anterior pituitary. TSH stimulates thyroxin release which causes cellular metabolism increase. Visceromotor responses are constricted blood vessels and piloerection. Somatic responses are shivering and warmth seeking. When it heats up, the anterior hypothalamus slows TSH release and blood is shunted toward the outside to dissipate heat. Also, the body will seek shade and panting or sweating can remove excess heat.
Part XII: Learning and Memory
Learning is the acquisition of new information or knowledge. Memory is the retention of learned information, either declarative or explicit (the memory for facts or events), or non-declarative or implicit, the most important of which is procedural memory (the memory for skills, habits and behaviors). The limit for storage on declarative memory is remarkably high, though we forget declarative memories relatively easily. Long term memories are those that we can recall a lengthy time after they were stored, and short term memories are those that are quickly forgotten if not stored via memory consolidation. However, short term memory could possibly exist in parallel to long term memories. It is usually studied using the digit span, the number of digits one can hold in memory after hearing them read; this is usually 7 plus or minus 2 digits. Amnesia is the serious loss of memory or the ability to learn. These include retrograde (memory loss of events prior to trauma � older memories are remarkably resistant though) or anterograde amnesia (inability to form new memories). If there is not associated cognitive deficit, it is dissociated amnesia. Transient global amnesia involves a sudden onset of anterograde amnesia for a brief period, followed by retrograde amnesia for the recent events preceding the attack. This is probably caused by temporary blood deprivation from learning/memory structures.
Engrams, or memory traces, are the physical representation or location of a memory in the brain. Lashley�s studies using lesions during maze learning saw that severity of memory deficits were related to the size and not the location of the lesions; thus, there was a case for distributed memory in learning. Hebb proposed that the internal representation of an object consists of all the cortical cells activated by the external stimulus, known as a cell assembly. These cells were supposedly reciprocally interconnected, and if activation extended long enough, consolidation would occur by a growth process that made these connections more effective. That is, if a small part of the assembly was later activated, the entire representation would be recalled. This meant that the engram was widely distributed and included the same neurons used to sense and perceive. Hebb then proposed that engrams, if based only on information from one sensory modality, would be localized within the areas of the cortex serving that modality (inputs that fire together wire together).
Just as electrical stimulation of somatic sensory cortex and motor cortex prompted reactions in the appropriate area of skin or muscle, it was proposed by Penfield that electrical stimulation of the temporal lobe would prompt memory retrieval, during his treatments of epileptic patients. A temporal lobectomy in monkeys showed that there were no perceptual deficits, but a �psychic blindness� seemed to belie any understanding or memory of what they were sensing. It seems that the temporal neocortex could be the site of long term memory storage; the medial temporal lobe seems to be for declarative memory processing or consolidation. It is made of the hippocampus and the three cortical regions around the rhinal sulcus (the entorhinal, perirhinal and parahippocampal cortex), which are critical to developing declarative memories. Input to these areas contains highly processed information from all sensory modalities that has passed through the cerebral cortex. From the hippocampus, information is sometimes passed back to the cortical association areas; output to the hypothalamus leaves through the fornix. To test memory formation of the temporal lobe, the delayed non-match to sample (DNMS) test is used. In it, animals are rewarded for displacing a sample object. After a delay in which the set is covered for a while, the animals are again rewarded if they can displace a different object from the one previously displaced. Those with lesions in the bilateral medial temporal area, as the delay increased, did much worse than those without. Also, lesions in the vicinity of the anterior and dorsomedial nuclei in the thalamus (within the diencephalon) or the mammillary bodies in the hypothalamus can cause deficits on the DNMS test. Axons from the hippocampus extend into the mammillary bodies and into the thalamic areas before they go to the cingulate cortex and other temporal lobe structures like the amygdala and inferotemporal neocortex, which projects to almost all frontal cortex. Korsakoff�s syndrome also implicates the diencephalon in memory consolidation; caused by thiamine deficiency usually present in chronic alcoholics, it is characterized by confusion, apathy and memory impairment. The anterograde amnesia is caused by lesions in the diencephalons, but the retrograde amnesia is caused by lesions elsewhere.
The hippocampus alone seems to have more diverse tasks. Using the radial arm maze, scientists were able to link the hippocampus to working memory, the retention of information needed to guide oncoming behaviors. The maze would consist of several arms with food at the end of each arm; with practice, the rat will travel down each arm just once and use visual cues (their working memory) to prevent going twice into any arm. Hippocampal lesions do not prevent learning; they merely prevent the efficiency in finding food that working memory would provide. Place cells within the hippocampus serve to locate the rat in a space through visual cues. In a certain location in the environment, place cells will fire. When away from that location, the place cells will stop firing. If the environment is changed, a short learning time span will pass before the place cells readjust and start firing in that same location, albeit changed. Thus, the firing of place cells is also reliant on visual cues. In humans, with video games, there is both hippocampal and caudate activation. The caudate activation is thought to reflect movement planning. One hypothesis proposes that the hippocampus also functions to store memories in such a way to relate all the things happening at the time the memory was stored; this is relational memory. The case can be made that the radial arm maze can by mastered through relational memory of all the visual and temporal cues, plus spatial memory from place cells. Odor memory also shows that some of this working memory does not rely on spatial cues alone. Using another version of the radial arm maze, scientists were also able to identify the striatum as the site for procedural memory. In this version, food was placed at the end of arms with lights, which could go on and off at any time. Food was never in any arms that were never lighted. Thus, the rat would have to learn, by habit, that food only existed at the end of corridors with lights. The striatum�s presence on the motor loop leads one to believe that the formation of a habit is coded in terms of sequences of motor behaviors. Diseases like Huntington�s attacks striatum neurons, and as a result, patients have difficulty learning tasks in which a motor response is associated with a stimulus.
The prefrontal cortex has already been implicated in executive function, or the capacity for complex planning and problem solving. Lesions on the prefrontal cortex have also shown that it may be involved in working memory as well, as test subjects have difficulty using recent information, such as in the Wisconsin card-sorting test, where cards are sorted by color or shape until the subject does it correctly, whereupon the system is changed and the subject must start again. The lateral intraparietal cortex (LIP) of the intraparietal sulcus seems to also be involved in working memory. It is thought to be involved in guiding eye movements, as result of the delayed saccade task seem to show. With this test, an image is flashed at a peripheral location though the eyes must be focused at a central location. Neuronal firing begins as response, and continues during a delay period until the fixation spot is turned off, whereupon it stops and the eyes make a saccadic movement to the remembered location of the target.
Procedural memories can be formed along simple reflex pathways that promote the learning of a motor response or procedure in reaction to a sensory input. One type of procedural learning is nonassociative learning, which is a change in behavioral response that occurs in time in response to a single type of stimulus. Habituation is learning to ignore stimuli that lack meaning. Sensitization caused by a strong sensory stimuli leads to intensification of responses to all stimuli. The other type is associative learning, using either classical or instrumental conditioning. Classical conditioning was discovered by Pavlov; it involves associating a stimulus that evokes a measurable response (the unconditioned stimulus) with a second stimulus that does not evoke this response (the conditioned stimulus). The response itself is called the conditioned response. This conditioning also requires proper timing; if the time intervals between stimuli are too long, the response is weak or absent. Instrumental conditioning involves the association of a motor act with a meaningful positive or negative stimulus, like pressing a lever for a food reward, or doing the same to prevent a foot shock. Timing is also involved with instrumental conditioning, as is motivation, so the neural mechanisms for this kind are more complicated than those for classical conditioning.
Scientists use invertebrate models to study learning, because they have much smaller neuron systems, identifiable neurons and circuits, and relatively simple genetics. Thus, neuron and gene maps can be created and compared against test subjects. Using the sea slug Aplysia californica, it was possible to study associative learning, as seen in habituation amidst the gill withdrawal reflex. Usually, a squirt of water on the siphon of the slug would initiate a quick retraction of the gill, but after several applications of the water jet, the reflex stops. Sensory information from the siphon travels along a nerve into the abdominal ganglion, where it is distributed to motor neurons and interneurons. One motor neuron, L7, innervates the muscles powering gill withdrawal. Habituation was found to be associated with a presynaptic modification, occurring at the synapse joining the sensory input to the motor neuron. After repeated electrical stimulation to the sensory neuron, the EPSPs would progressively decrease in size; this is caused by inactivation of N-type Ca channels in the axon terminal of the sensory neuron, resulting in reduced presynaptic calcium entry per action potential and transmitter release with repeated stimulation (synaptic depression). To understand more about gill withdrawal, scientists studied sensitization of the reflex through stimulation of the head of the slug. This activates L29, which synapses on the axon terminal of the sensory neuron. Serotonin, or 5-HT, is released, which binds to a G-protein coupled metabotropic receptor on the sensory axon terminal. This activates second messenger cAMP, which activates protein kinase A, which can then phosphorylate potassium channels, closing them. This allows the membrane voltage to stay above threshold longer, allowing voltage gated calcium channels to stay open longer, causing more glutamate transmitter to be released on the motor neuron.
An astonishing discovery occurred when it was found that sea slugs could also be classically conditioned. The conditioned stimulus was the stimulation of the siphon, which results in gill withdrawal. If the conditioned stimulus precedes the unconditioned stimulus, or stimulation of the tail, by less than 0.5 seconds, the slug can learn to withdraw their gills upon stimulation of the tail. More precisely, learning occurs during the meeting of the presynaptic influx of calcium during the conditioned stimulus and the G-protein coupled activation of adenylyl cyclase during the unconditioned stimulus. Memory occurs when potassium channels are phosphorylated and neurotransmitter release is enhanced. These studies have only found the cellular correlates but not the cellular basis of learning; they have been useful in providing candidate molecular mechanisms. Overall, as have the following vertebrate studies, they show learning and memory can result from modifications of synaptic transmission; synaptic modifications can be triggered by the conversion of neural activity into intracellular second messengers; and memories can result from alterations in existing synaptic proteins.
In vertebrate models, the cerebellum has become the focus of research, as it is a site for motor learning where modifications of synaptic connections are made to correct failed motor actions. Within the cerebellar cortex lies two layers of cells, the Purkinje cell layer and the granule cell layer, separated from the surface by a molecular layer lacking soma. The Purkinje cells extend flattened dendrites into the molecular layer and their axons synapse on neurons within the deep cerebellar nuclei, which are the major output cells of the cerebellum. Their NT is GABA, so they exert an inhibitory influence on cerebellar output. Inputs arise from the inferior olive, which integrates information from muscle proprioceptors. The axons are called climbing fibers, because they twist around the Purkinje fibers; these make hundreds of excitatory synapses that strongly activate the postsynaptic Purkinje cell. The granule cells receive input from mossy fibers. These cells are small and numerous, and extend into T branches called parallel fibers in the molecular layer. These fibers encounter many Purkinje cells; one Purkinje cell can receive one synapse each from up to 100,000 fibers. By the Marr-Albus theory of motor learning, plasticity of the parallel fiber synapse occurs if it is active at the same time as the climbing fiber input to the postsynaptic Purkinje cell. As a test of parallel fiber synapse effectiveness, researchers stimulated the parallel fibers and measured the EPSP in the Purkinje cell. They then stimulated both kinds of fibers to induce synaptic plasticity, and then just the activated parallel fibers (input specificity), which resulted in a smaller postsynaptic response called long term depression or LTD. LTD is caused when three intracellular signals are caused at the same time: climbing fiber activation strongly depolarizes Purkinje cell dendrite, activating voltage gated calcium channels; parallel fiber activation leads to sodium entry through activation of AMPA glutamate receptors; and the activation of the metabotropic glutamate receptor, which leads to activation of diacylglycerol (DAG) via G-protein and consequently, protein kinase C. This is the learning portion. Memory occurs when somehow, AMPA channels are closed/internalized and EPSPs are depressed.
The hippocampus is extremely important in memory. Penfield's experiment showed hippocampal stimulation evoked memory, and damage caused profound memory impairments. Within the hippocampus lie two sheets folded onto each other: the dentate gyrus and Ammon�s horn, which contain divisions CA1 and CA3. Input to the hippocampus from the entorhinal cortex enters through the perforant path and synapses on the dentate gyrus, which gives rise to mossy fibers that synapse in CA3. Axons leave CA3 and branch, one leaving the hippocampus through the fornix and the other, the Schaffer collateral, synapsing in CA1. Using brain slice preparation, in which slices of hippocampus have been removed from the brain and kept alive, scientists were able to study synaptic responses resulting from electrical stimulation. Some were able to demonstrate an effect called long term potentiation or LTP, where brief high frequency electrical stimulation of a hippocampus excitatory pathway produced a long lasting boost in strength of synapses. Requirements for LTP include cooperativity (coactive synapses must cooperate to produce enough depolarization), input specificity, and the situation that synapses be active at the same time that the postsynaptic CA1 neuron is strongly depolarized.
The Schaffer collateral produces the glutamate that binds to the two different kinds of glutamate receptors on the CA1 neuron: the AMPA receptor, which is a ligand-gated channel that allows an influx of sodium that causes EPSP's; and the NMDA receptor, which is blocked by magnesium ions at room temperature. Opening the NMDA receptor channels requires glutamate binding and enough depolarization of the postsynaptic membrane to displace those Mg++ ions. Calcium can then enter and activate protein kinase C and calcium-calmodulin-dependent protein kinase II (CaMKII), which leads to kinase phosphorylation of AMPA channels that enhances the responsiveness of AMPA to glutamate - meaning they stay open longer when activated in the future. At the same time, new AMPA receptors are inserted into the postsynaptic membrane. The rest of the calcium activates synthesis of retrograde messengers such as NO, which diffuses to the presynaptic cell and increases transmitter release. LTP cannot occur if NMDA, PKC or CaMKII are inhibited. From here, it seems as if phosphorylation of AMPA leads to a protein change that increase channel ionic conductance, and at the same time, new AMPA receptors are inserted into the postsynaptic membrane. The only affected cells are the ones at the site of synaptic contact, and thus synapse-specific.
Under the BCM theory, hippocampal LTD, like LTP, is triggered by postsynaptic calcium entry through the NMDA receptor. With low depolarization, not all the magnesium is removed from the channel and calcium can only trickle in. With low elevations in the amount of calcium, only protein phosphatases are activated instead of the kinases. This then leads to dephosphorylation of AMPA receptors and internalization of AMPA receptors at the synapse. Theoretical research shows LTP and LTD can contribute to formation of declarative memories. Further research shows that NMDA-receptor-dependent synaptic plasticity might occur throughout the cerebral cortex in the same way. Evidence linking LTP and LTD to memory comes through the Morris water maze, where a rat must look for a submerged platform in order to escape. Hippocampal lesions prevent the rat from learning to master the maze; further studies showed blockage of NMDA receptors did the same. Other studies show increases in the number of NMDA receptors generate enhanced learning ability.
Memory can result from experience-independent alterations in synaptic transmission, usually by changing the number of phosphate groups. However, this only lasts while phosphate groups remain attached to the protein; phosphate groups are eventually removed and proteins are eventually replaced. Mechanisms for long-term memory include persistently active protein kinases that no longer need second messengers, which must be followed by synthesis of new protein to assemble new synapses. One kinase, CaMKII, needed for induction of LTP in CA1, is made of ten subunits that each catalyzes phosphorylation in response to rises in Ca-calmodulin. Each subunit is made up of a catalytic region that conducts the phosphorylation, and a hinged regulatory region that keeps the enzyme off when the second messenger is not around. However, if initial activation is sufficiently strong, autophosphorylation (by neighboring subunits) can occur faster than dephosphorylation and maintain synaptic potentiation that way. This idea is known as the molecular switch hypothesis. As the conversion to long term memory occurs, it has been found that there must be workable protein syntheses during the period of memory consolidation for the process to finish properly; these new proteins maintain the synapses until it has been converted. Memory strength can also be controlled through modulation of gene expression by the cAMP response element binding protein (CREB). CREB binds to cAMP response elements (CRE) and regulate the expression of neighboring genes. CREB-2 acts as a repressor until it is replaced by the activator CREB-1, which must be phosphorylated by protein kinase A before it can allow transcription to occur. In Drosophila studies, extra amounts of CREB-1 allowed flies to attain better memories; thus, the more CREB-1, the stronger the memory retained. Also, long term memory has been associated with the formation of new synapses, changing the structure of the nervous system. However, this can also lead to a decrease in the number of synapses. Generally, structural plasticity is highest when young and much less flexible in the adult years.