Lecture 1:
Sensory Transduction, Sensory Arrays and Topographic Maps:    Chapters 9-5, 10-1, 10-2, 10-3
 

Nerve fibres can be activated directly (as in funny bone example), but note the extremely high intensity required to bring a fibre to threshold by direct activation.

Transduction is the process by which the energy of a sensory stimulus is converted to a more efficient form for the activation of the sensory nerve fibre.
Types of Receptor:
1. Mechanoreceptors:
Mechanism of transduction still obscure, but involves cationic channels which may be directly sensitive to mechanical stimuli. Shortest latency of all receptor cells.
A. Tactile Receptors in the skin:
A variety of specialised receptors, often named after the scholar who first described the morphology
1.Pacinian corpuscles; Onion-skin arrangement; glabrous skin; high temporal (in timing) fidelity to vibration; can detect minute (1mm) displacements; important for Braille; ìacceleration detectorsî
2. Iggo corpuscles; Like Pacinian but on hairy skin; ìintensity detectorsî
3. Meissnerís corpuscles (glabrous) & Follicle receptors (Hairy); adapt rapidly so that most effective stimulus is rapid rate of indentation; ìvelocity detectorsî.
B. Hair Cell Receptors:
Transduce shearing forces: Derived phylogenetically from hair cells responsible for the detection of fluid motion past the lateral line system (amphibians, fish and other anamniotes).
1. Cochlea; 1 row of Inner Hair Cells (passive frequency coding) and 3 rows of Outer
 Hair Cells (supplying frequency-specific electromechanical feedback).
2.  Cupula: Hair cells embedded in gelatinous bulb which bends with fluid motion in the  semicircular canals.
3.  Otolith: Hair cells embedded in gelatinous matrix containing apatite crystals (otoliths). May be involved in detection of substrate vibration, acceleration of the head due to gravity.
C. Muscle Spindles:
Once thought not to contribute to sensation, but now known to provide important proprioceptive (internal body sense) information. Very sensitive to vibration, hence illusions of movement if vibration is applied to a muscle during movement.
2. Photoreceptors:
Receptor protein (rhodopsin is the archetype molecule) is a G-protein linked protein with considerable versatility. Like other G-protein linked transduction systems, response is amplified (one photon per photoreceptor can be detected by the central nervous system) and can also undergo adaptation (note the 9-10 log unit range of visual sensitivity). In vertebrates, photon capture leads to a closing of the cationic channel associated with the opsin molecule, along with release of second messenger which diffuses to close more channels. This dependence on diffusion makes for a long latency response.
Rods: Operate in range 0-5 log units (darkness to dusk); rhodopsin 560nm
Cones: Operate in range 5-8 log units (dusk to bright sun); 3 photopigments, 45nm (ìblueî), 510nm (ìgreenî) and 570nm (ìredî).
Pineal Photoreceptors: Sensitive enough for a sparrow to detect moonlight through its skull.
3. Chemoreceptors:
Tongue Taste-buds: pH, saccharides, cations, bitter alkaloids.
Hypothalamus: pH, monosaccharides,.
Arterial Chemoreceptors: pO2
4. Thermoreceptors:
Skin: Both hot and cold detectors. ?some overlap with nociceptor.
Hypothalamus: Both hot and cold receptors; involved in thermoregulation; sensitive to pyrogens.
5. Nociceptors:
Note distinction between nociception (the detection of tissue damage) and pain ( a more complex state with elements of motor output or decision making overlay the sensory state). Nociceptors correspond structurally to free nerve endings, but note that physiology is much more heterogeneous than anatomy, with some responsive to thermal, others to mechanical, damage.
6. Electroreceptors:
Recently described in the platypus bill and echidna snout, but note that they are well-described from electric fish and from sharks. Enable the detection of the minute electric currents associated with neuromuscular activity in prey.

Note that underwater mechanoreception and electroreception are combined by the platypus bill and the enormously-increased trigeminal pathway to somtosensory cortex. In cortex therre are bimodal neurons that respond to both electrical stimuli and mechanical stimuli that are separated by a specific time delay. This gives the platypus information about the distance of the prey, whose tail flick generates both an electrical wave that travels very fast (close to light speed) and a mechanical wave that arrives later, depending on the distance to the platypus. In this "Thunder and Lightning" mechansim, the platypus calculates teh distance of the prey in total darkness.

7. Magnetoreceptors:
Their presence in vertebrates only speculated upon at present, based on behavioural responses of both birds and insects to earth-strength magnetic fields. Note that magnetotactic bacteria have crystals of magnetite inside which physically orient these motile organisms in the earth's magnetic field.
Topographic Maps
Sperry demonstrated point-to -point connections between retina and tectum; Sperryís postulated ìchemoaffinityî mechanism has now been verified with antibodies to a gradient of chemical labels specifying a topographic array of cell-to-cell connections. Topographic organisation is a general feature of all interconnections in the brain, but note that the kind of information being represented across the map may not always be known. Some maps are generated directly by point-to-point connections from the sensory periphery to the brain; other maps cannot be generated in this way and must be synthesised centrally (computational maps).

Point-to-Point Sensory Topographical maps:
A. Retinotopic Map: Visual System
Maintains the two-dimensional relationships in the retina; orienting response when linked to a ëmotor mapí of output connections such as the superior colliculus.

B. Tonotopic map: Auditory System
One-dimensional map of cochlear output so that sound frequency is represented continuously across the surface of most nuclei in the auditory pathway.

C. Somatotopic Map:
Representation of the body surface receptors (mostly skin).
Note that these maps (Homunculi) are plastic and can adjust to the loss of unuts. In the famous example from the work of Ramachandran, a "phantom limb" of an amputee has referred sensation from stimulation of the face, as a result of the homunculus "filling in" the missing arm inputs with inputs from the face which is adjacent in the representation (Click here to see rough diagram of this process).

Computational (Centrally-synthesised) Maps:
These maps have to be generated by the brainís own computations, rather than arising as a consequence of connections to a sensory surface which is already ordered.
i. Auditory space amp: inferior colliculus;  neighbouring neurons have neighbouring
preferences for sound location (like a retinotopic map); generated in a complex way by a continuous array of sensitivity for differences between the sounds coming to the two ears.
ii. Orientation map: visual cortex; continuous variation from neuron to neuron across the cortex in the preferred orientation of a visual edge.
 

Lecture 2:
Visual Stabilisation     Chapter 5-4

Visuo-Motor Stabilisation:

"Eye movements evolved to keep the eyes still"  David A. Robinson.

Although this statement has its paradoxical side, given that we primates have intense saccadic activity, if we ignore these rapid square wave eye position changes that are clearly aimed to change the object of regard as quickly as possible, it is obvious that gaze is very stable despite destabilising inputs such as head movements.

There are two main visuo-motor stabilising reflexes (VOR and OKN), but note that each one, especially the OKN, can be influenced by higher function.

1. VOR: Vestibulo-Ocular Reflex:

Disynaptic Arc:

Vestibular Hair Cell ...........> Vestibular Nucleus............> Oculomotor Nucleus
 

 .Short latency (Fast conduction, short axons and short latency of mechanotransduction).
 . Best at high head velocities
 . Adjustable gain
 . Cerebellum required for gain adjustment

2. OKN: Opto-kinetic Reflex (Optokinetic nystagmus)

Multi-synaptic reflex arc from direction-selective ganglion cells in the retina to oculomotor system.

 .Photoreceptors......1....>Bipolars.........2.......>Direction-selective ganglion cells.......3........>Accessory Optic Nuclei..........4.......> Inferior Olive.......5........>Oculomotor Nucleus

 . Long latency (multiple synaptic station, fine axons, v. long latency out of photoreceptor)
 . Excellent at slow head velocities (accessory optic system can detect movement of sun across sky!)
 Three classes of direction-selective ganglion cells (for the three possible kinds of rotation, pitch, roll and yaw) connect to the 3 divisions of the accessory optic system, which in term connect to the three divisions of the VOR system, one for each pair of eye muscles.
 . Provides an error signal to the cerebellum.

click here for Vestibulo-ocular reflex circuit.

Lecture 3:
Cerebellum:       Chapter 12.1

click here for "Colour Me" cerebellar circuit.

Vision                Chapter 9
 

Vision           Lecture 4

Retinal Image Formation:
Cornea contributes 40 dioptres to 60 dioptres total of refractive power of eye; hence need for special optical arrangements underwater where cornea is eliminated.
Lens is naturally elastic but in human eye is usually flattened by the tension of the zonulat ligaments so that the retinal image is in focus at infinity. During accommodation, contractcion of the ciliary muscles acts to relieve the tension exerted on the lens by the zonular ligaments so the lens bulges under its own elasticity to increase its curvature and bring the retinal image into focus for near targets.
Myopia. Eyeball too long for refractive power of lens and cornea; retinal image from infinity focussed in front of retina; cannot be accommodated for and is therefore unknown in wild animals which are usually 1-2 dioptres hyperopic.
Hyperopia. Eyeball too short for its refractive power; can be accommodated since accommodation can provide an extra 10 dioptres of power.
Presbyopia. As the lens ages, it loses its elasticity. There fore a reduction in the extra lens power provided by allowing the lens to assume its maximal curvature when the ciliary muscles act to decrease the zonular tension.
Dioptre. Lens power needed to bring rays from infinity into focus at 1m. Example: human accommodative range is normally 10d. Thus the ìnear pointî is 1/10m. In presbyopia this range is progressively reduced; with a range of only 4 dioptres the ìnear pointî would go out to 1/4m.
The Duplex Retina
 Rods Cones
One photo[pigment 560nm Three photopigments 450; 600; 650nm
0-5 log unit range of sensitivity 5-8 log units of sensitivity
Absent from the fovea in humans Concentrated in the fovea
High sensitivity, low resolution Low sensitivity, high resolution
Highly convergent pathway to bipolars  One-to-one connections to bipolars and ganglion and ganglion cells cells

Purkinje shift:
At dusk, when retinal function is shifting over from cones to the more sensitive rods, both are operational for a while. During this time, greens are enhanced because of the greater sensitivity of the rods to this part of the spectrum. At night ìall cats are greyî because there is only one kind of rod, but at dusk, there is just enough light for the 3 cones to signal colours, at the same time that the rods are responding most strongly to medium wavelengths, which therefore look brighter.
Parallel Visual Processing
Vision is a complex task, whose difficulty is belied by the ease with which we appear to carry it out. The task is divided up into sub-tasks, each of which is carried out by different classes of visual cells with different pathways. For example, at the level of the retinal ganglion cell, there are different ìtrigger featuresî for each cell.
 

Trigger feature
The combination, in space and time, of photoreceptor activation which is necessary to activate the retinal ganglion cell. Since the ganglion cell receives a variety of both excitatory and inhibitory inputs, a particular pattern of stimulation must be specified. This spatio-temporal pattern is the trigger feature.

Example of Trigger Feature in Different Retinal Ganglion Cells
1. Local contrast detectors (concentric, or centre-surround antagonistic receptive fields) which are sensitive to local differences in illumination but which are insensitive to the total amount of light: these are the simplest in organisation and the most common type of feature detector in the mammalain retina. They project into the geniculo-striate pathway.
2. Direction selective neurons: respond only to movement in a particular direction.
There are 2 kinds:
i) ON-type have slow preferred velocities and project into the accessory optic pathway: they are divided into 3 direction classes that correpond to the 3 axes of eye rotation, semicircular canal rotation and oculomotor organisation.
ii) ON-OFF direction selective ganglion cells have high preferred velocities and project widely in the visual pathways of lagomorphs and rodents, but seem to be absent from carnivores, ungulates and primates.
3. Local Edge Detectors and Orientation Detectors: respond to very fine detail on the far horizon. Prominent only in prey animals which scan the far horizon for approaching predators. Project to the optic tectum. Similar orientation detectors are found in the visual cortex of all mammals.
4. Fast motion detectors: well described in the rabbit retina; respond best to low-contrast, very rapidly-moving shadows I the upper visual field. Have fast conduction velocity into the brain where they probably trigger escape &/or freezing behaviour.
5. Luminosity Detectors ("tonic units"): respond to changes in absolute illumination, in contrast to the local contrast detectors, on account their absent surround mechanism. Very few in number, they project into the hypothalamic suprachiasmatic nucleus where they act to synchronise the circadian clock and into the pretectal nuclei where they are involved with pupillary control.
6. Dual Opponent Colour Detectors: Can detect a particular colour irrespective of the composition of the incident light (ìcolour constancyî). Project to midbrain.
Targets for Retinal Information
1. Hypothalamus.
Suprachiasmatic nucleus. Circadian rhythm. Input from tonic retinal ganglion cells which signal light intensity (and therefore dawn).
2. Thalamus:
a. Pulvinar: Contributes to the "dorsal stram" of visual processing.
b. Lateral Geniculate Nucleus. Layered arrangements of hemiretinas of both eyes. Stereoscopic vision. Sandwich-like arrangement so that a toothpick would mark neurons with projections to teh same part of visula space, even though they are on two different retinas.
Six layers in primates provide binocular interaction for different ìchannelsî of visual information such as colour, size and motion.
3. Pretectal Nuclei. Mediate the near-triad; pupil constriction, accommodation, convergence. Binocular input.
4. Optic Tectum (Superior Colliculus). Many different layers with complicated output connections mediating the orientating response. Has various maps, in register, of visual and auditory space as well as motor maps for the production of orienting movements of the head and eyes.
5. Accessory Optic Nuclei. Three different nuclei corresponding to the three axes of rotation of the semicircular canals. Optokinetic stabilisation. Input from 3 classes of direction selective retinal ganglion cells.

Geniculo-Striate Pathway:
Highly developed in primates and the only visual pathway in most textbooks, but by no means the only one. This pathway is highly developed in those species with frontally-placed eyes.
Retina  ..........> Lateral Geniculate Nucleus..................> Striate Cortex
Note that there is no relay in the midbrain. Note also that this pathway for binocular visual processing avoids complex feature analysis until after the pathways from both eyes converge. In other words, of the many types of trigger feature, only the concentric (centre-surround opponency) variety (1 in the above list) project into the geniculo-striate pathway.

Tectofugal Pathway:
More highly-specialised than the geniculo-striate pathway, with input from many of the more complicated retinal ganglion cells (2-5 in the above list) which can directly trigger behavioural circuits in the midbrain. Massively developed in lateral-eyed animals like the ungulates.
Retina.................> OpticTectum (S. Colliculus) ...............> Pulvinar.................> Extra-Striate Cortex

Tecto-Fugal                                                               Geniculo-striate

Extra-striate cortex                            Neocortex                            Striate Cortex

          ^                                                 ^
           |                                                              |
           |                                                              |
 
 

Pulvinar (mammals)                           Thalamus                            Lateral geniculate
Rotundus (birds)

           ^
           |
        |
Optic Tectum                                     Midbrain                         ^
(superior colluculus)                                                                   |
                                                                                                    |
           ^
           |
        |
Ganglion Cells )                                                                             (Ganglion Cells
Bipolar Cells )                                    Retina                                  (Bipolar Cells
Photoreceptors)                                                                              (Photoreceptors

Lecture 5:

Lecture 5:
Hearing                 Chapter 12
 
 

Hearing Lectures
Schmidt and Thews 12.1, p289-292
Figures 12-6,12-7,12-8,12-9,12-12,12-125
 
 

Hair cells evolved to detect the minute movements of fluids produced in the aquatic environment. For the detection of airborne sound vibrations in the low impedance medium of the air are matched to the much higher impedance of the fluids in which the hair cells are immersed. Since the impedance of the fluids of the inner ear is about 135 times that of air, if sound energy were presented directly via an air fluid interface, 97% would be reflected and only 3% transmitted. Because of the impedance matching function of the middle ear an estimated 60% of incident energy is in fact transmitted into the cochlea. The middle ear thus acts as an impedance transformer which depends on the fact that tympanic membrane has an area 17 times that of the footplate of the stapes and upon the fact that the long process of the incus is somewhat shorter than that of the malleus giving a mechanical advantage by extra leverage. Pressures at the footplate which are delivered to the fluid of the inner ear are therefore 22 times greater in man than the pressure of sound which moves the tympanic membrane.
Conduction deafness corresponds to a defect in the middle ear and can therefore be cured by providing high pressure low amplitude stimulation directly to the bone which then drives the inner ear fluid (bone conduction). Conduction through the middle ear can also be reduced under normal circumstances by the action of the stapedius muscle which pulls on the neck of the stapes and tends to immobilise the footplate in response to sudden loud sounds.
Frequency-tuning of Basilar membrane:
Extremely sharply-localised vibration within basilar membrane (likened by Helmholtz to piano strings).
 Basal end - high frequencies
 Apical end - low frequencies
Three contributing factors:
a) Travelling wave in basilar membrane. Low frequencies travel further along membrane than high. Accounts for high to low array and for the low frequency ëaproní of low frequency sensitivity on tuning curves of individual auditory nerve fibres.
b)  Intrinsic oscillatory properties of hair cell membrane which give intrinsic electrical tuning for frequency. This varies systematically from cell to cell.
c) Electromechanical feedback to basilar membrane motion from outer hair cells, which are motile themselves and can thereby locally increase the motion produced by a given frequency and hence increase sharpness of tuning (probably responsible for acoustic emission or "objective tinnitus" where sound actually emanates from the ear by a reverse driving of tympanic membrane and ossicles from inner ear motion).

A Hair cells Frequency tuning, tonotopic array
B Spiral ganglion cells Sensory relay neurons
C Dorsal cochlear nucleus Start of dorsal acoustic pathway for sound
  quality
D Ventral cochlear nucleus Start of bilateral pathway for sound location
E, F Superior Olivary Complex All cells strongly bianural
E Medial Superior Olive Tonotopic array emphasises low frequencies.
  Phase information about stimulus accurately
  preserved. Beginning of azimuthal location
  analysis based on inter aural time differences.
F Lateral Superior Olive Tonotopic array emphasises high frequencies EI
  binaural interaction. Intensity coding emphasised.
  Beginning of location analysis based on interaural
  intensity differences (in barn owl gives elevation).
G N. lateral lemniscus Relay
H Inferior colliculus Major midbrain structure responsible for
  orientation to sound. The various auditory
  pathways come together here. Complex structure
  and function combining analysis of both quality
  and location (note that these two separate analyses
  can help each other as in the ëstream segregationí
  phenomenon of sorting out individual voices
  from the babble of a cocktail party).
I Medial Geniculate Thalamic relay for the many different auditory
  cortical areas. Plays a major role in gating the
  transfer of signals to the cortex according to
  arousal state.
J Auditory cortex At least six different areas, some tonotopic, for
  analyses of sound not yet well-defined, except in
  bats where the function of each area can be
  directly related to the needs of bat (e.g. echo-delay
  area for range of prey, Doppler-shift area for
  detecting frequency-modualtion of wing-beating
  prey, etc.). In man, probably some areas involved
  in phonemic processing.
 

Lecture 6
Sleep and Circadian Rhythms      Chapter 6-2, 6-3

Why sleep?
Circadian rhythm does not require environmental input and is therefore predictive of light/dark cycle without need for sensory cues.
All living organisms (even cyanobacteria) have circadian clocks, to budget time effectivley, to partition rest-repair from risky exploration etc and to reduce the need for sensory cueing about the daily cycle. Asking why one sleeps becomes a less urgent question in this evolutionary context of daily rhythms.

Transcriptional Clocks:
Mammals, flies, fungi and cyanobacteria all have transcriptional clocks that work in a similar way, although has a different pair of genes. In mammals, the genes are per (periodic) and tim (timeless) whose transcription leads to the expression of 2 cytoplasmic proteins (PER and TIM) that dimerise to produce a hetrodimer that binds to DNA and turns off the transcription of its own genes. It is still not clear how one generates a rhythm as long as 25 hours, but it is thought that one of the keys is the very low concentrations, early in the cycle, of PER and TIM that are under constant degradation.

                                                         Slow Wave Sleep                                                REM Sleep

EEG                                         Synchronised; sleep spindles;                           Desynchronised as in waking (hence "paradoxical" sleep
Skeletal muscle                        Relaxed but active every ~10 min                      Atonic (except for eye muscles)
Temperature Regulation           Good                                                                 Poor
Upper motor neurons               Like waking but more sluggish                         Strong synchronised bursting activity
Dreams                                    Absent (N.B. sleepwalking in SWS phase)       Dreams in this phase: majority have negative affect
Autonomic NS                        Parasympathetic system dominates                     Sympathetic activity dominates
                                                Heart rate down                                                  Heart rate & blood pressure up, Growth Hormone spurts,
                                                                                                                           Penile erection
Hemisphere active                    ?Left hemisphere                                                ?Right hemisphere

Jouvet's Phasically Flying Cat:
I can't find any good visual material about this remarkable experiment showing that REM sleep is accompanied by frenzied activity if one interrupts the descending pathway reponsible for the atonia of REM (and sleep paralysis). Click here for links to the literature. Only for the keen and not examinable.

Thalamic Gate:
Sensory transmission through the thalamus is subject to a gate that is closed in SWSleep. The gate involves inhibitory interneurons that are held down in wakefulness by activating systems that have an inhibitory action on these interneurons (e.g. the noradrenaline input from the locus coeruleus). With the onset of SWSleep, the activating systems fall silent and the inhibitory interneurons escape from tonic inhibition. New ion channels also become active at this time so that long bursts are favoured. The result is that thalamic neurns whose activity is normally desynchronised from each other by fact that they respond to slightly different sensory stimuli, now start firing in synchronous bursts with long silent periods between. This synchronous activity gives rise to the "spindle" that visible in the EEG,

Oxidative Damage:
Sleep is directly related to metabolism. Almost perfect mathematical relation between metabolic rate and sleep time.
Birds sleep less then mammals, an apparent contradiction of the idea that sleep is related to metabolism, but note that birds also have more efficient mitochondria (mammalian mitochondrial radical production is 3% compared with avian production of 0.3%). In other words, the need to sleep is explained by the accumulated oxidative damage, which would be less in birds because of their superior mitochondria, even though they have a higher metabolism.

Active radicals (Reactive Oxygen Species...ROS):   O- (superoxide), OH- (hydroxyl ion), H202 (peroxide).

Dealing with Oxidative Damage: 3 strategies: Quarantine; Scavenge; Repair
All radicals (ROS species) oxidise proteins, lipids and nucleic acids. Each has a slightly different pathlength within the cell before being quenched by the tissue. There is a huge diversity of strategies that have been adopted by organisms to deal with these nasty poisons. They present a special problem for the brain, which produces more of them than any other organ in the body by virtue of its high oxidative metabolism.  Moreover, the brain is post-mitotic and cannot conveniently mark a badly oxidised cell for removal in the same way that occurs in liver and skin.

Here are some general principles for handling oxidative damage:-

1. Quarantine: Mitochondria can be located away from sensitive sites (e.g. spermatogonia of testis to limit damage to the germ plasm; in the inner segment of photoreceptors away from the outer segments where oxidation of photopigment would increase noise of vision).

2. Scavenge:
A range of molecules and enzymes act to buffer the worst effects of the active radicals. The superiority of the avian mitochondrian is presumably related to its much higher concentrations (and perhasp even novel forms) of scavengers.
Endogenous:
a. Superoxide dismutase (SOD). These metallo-enzymes come in lots of different flavours, linked to different metal ions (e.g. manganese, chromium). The mitochondrion is packed with one version and others are cytoplasmic.
b. Glutathione (GSH). The most ubiquitous of all the scavengers and quantitatively the most important. Key role in protecting proteins from oxidation.
c. Melatonin: Very efficient scavenger of OH-. Stable, small molecule that diffuses freely throughout body. Discovered by most living organisms (!concentrations in green leaves). Huge concentrations in young humans (more than can be accounted for by the pineal). As well as scavenging OH-, now has a role in signalling (e.g.photoreceptor shedding, immune system upregulation) durng sleep. Amount produced falls off linearly with age.
Exogenous:
Vitamin C: Important in the aqueous medium; concentrated in skin, brain.
Vitamin E. Membrane action to guard against oxidation of lipids.
Proanthocyanidins: Like melatonin, crosses blood-brain barrier, so may be especially important for brain.

3. Repair:
Some proteins (chaperonins) may be involved in the repair of other oxidised proteins in the brain. Note again that putting damaged components into the garbage is not always available to the brain in the same way as it might be for other tissues....hence a high premium may set on repair of damaged components.

Adjusting a damaged (i.e. oxidised) circuit is relatively easy in some cases. e.g. the VOR is constantly being updated by the plastic mechanism that uses visual information about retinal slip. So oxidative damage could easily be compensated, "on the run" as the brain is being used.

But note that declarative memories, many of which are one-off experiences, cannot be repaired in this way. Instead some internally-generated reference signal (?dreams) must be generated to see if rarely-activated memories have been damaged or not. This may also necessitate that the machinery (i.e. brain) be shut down during that time (i.e. sleep).

Neurodegenerative Diseases all involve some disturbance of the mechanisms for avoiding oxidative damage.
Friedrich's Ataxia lack's a ion pump that normall keps the mitochondrion free of ferrous ions. A high concntration of ferrous ions leads to increased oxidative damage and death of highly active neurons in the cerebellar pathways.
Alzheimer;s Disease:
Oxidative cell death of the aminergic fibre systems (e.g. locus coerueus, raphe, basal cholinergic n.) that must supply the expanded cortex of primates with transmitters and modulators from a cell group the same as found in rodents with a tiny neocortex.
Parkinson's Disease:
Dopaminergic cells of the substantia nigra undergo oxidative damage and death that is a long term consequence of viral infection or ingestion of toxin.
Retinitis pigmentosa involves degeneration of photoreceptors. This may be genetic (the complex biochemical pathways that maintain the high energy useage of the photoreceptor have numerous weak links, any one of which can have a genetic predisposition to break) or environmental (~50% are not genetic). Experimentally oxygen deprivation and anti-oxidants delay the progression of the disorder (although note that exogenous melatonin, which is produced by the eye, seems hasten progression).

Lecture 8. Synaptic Integration: The Pulse-Step Problem::

Summation and Inhibition: Fig. 3-10
Motoneurons and the H-reflex:   Chapter 5: fig. 5-7
Oculomotor neurons: Saccade: Fig. 11-2
 

Summary of Lecture 1:
 

Theme:   Synaptic integration using motoneurons as a model

1. Motoneurons: large neurons that act as "power amplifiers" to translate information-processing decisions into action (cf. the much smaller neurons that can carry out sensory processing)
 1. H-reflex: monosynaptic extensor reflex
 2. Oculomotor neurons.

2. Eye movements: (Note that they evolved to keep the eyes STILL!, because of the slow reaction time of photoreceptors)
 a. Saccades:
    French for "jump". Saccades are so fasr that they are accompanied by a "crack" that is audible if one places a stethoscope on the eye.
    While saccades seem to break the rule that eye movements keep the eye still, their extreme rapidity means that the time when the eye is     moving      is kept to a minimum...and the eye is perfectly stable between saccades if the pulse-step matching process is functioning normally.
 b   Visual stabilisation reflexes:
  Optokinetic nystagmus
  Vestibulo-ocular reflex

3. Mechanical Problem of the "pulse+step" for saccades:
    This engineering problem is one of the most sophisticated facing the brain: it is very sensitive to disturbance
 a. Firing rate depends upon eye position: a step change in firing rate of the oculomotor neuron will lead to a step change in eye position
 b. Superior colliculus provides synaptic summation proportional to eye position
 c. Burst neurons provide the burst that is necessary to "kick" the eye to the new position that would otherwise be reached too slowly ("undershoot") if total reliance was placed upon the step chane in firing rate.
The cerebellum has the task of adjusting the duration of the burst of fring so the pulse is exactly matched to the step. This fine adjustment is disturbed first in disease and poisoning of the hindbrain.

Lecture 9:  Patterned Motor Output:
Hypothalamus                      Chapter 16-5

University of Queensland
Department of Physiology & Pharmacology
 

PL227 Lecture 4
 

Patterned Motor Output: Hypothalamus Professor J. Pettigrew
 

Medial Hypothalamus

® Reciprocal connections with lateral hypothalamus (thereby reccives indirect sensory input).
® Directly monitors CSF and blood parameters
® e.g. temperature electrolyte, glucose, and hormone concentrations.
® Efferent connections  - neuronal to neurohypophysis
- Hormaonal (RFís) to adenophpophysis

Lateral Hypothalamus:

* Reciprocal connections to medial hypothalmus, limbic system, mesencephalon (limbic midbrain) and upper brainstem.
* Receives afferent inputs from body surface and interioe by way of thalamus and limbic midbrain: includes ìefference copyî information about motor state.
* Efferent connections to the autoomic and somatic nuclei in the brainstem and spinal cord via multisynaptic pathways in reticular formation.
* e.g. medullary autoregulatry neurons for cardiac output.
*
Some Principles of Operation of Motor Systems , derived largely from studies of small nural systems in invertebrates, but likely to apply generally.
1) ìMotor Tapesî or ìFixed Action Patternsî:
Preprogrammed, sterotyped temporal patterns of coordinated motor activity, which unfold until completion once sequence is initiated.
e.g. (i)  ìQuiet Pounceî attack by a cat on a small whitish ellipsoid target (ìmouseî) which
   follows electrical stimulation of the lateral hypothalamus.
(ii) During grooming by a mouse, eyelid closes a few milliseconds before paw passes
 over the eye, even when forelimb has been amputated.

2) Open-loop control: Sensory feedback from the consequences of the movement are not
 necessary for the generation of the patterned motor output. The rhythm is determined
 by the properties of the circuit (see (3)) and does not require sensory input for the
 relative timing between bursts of activity in antagonists and agonists.
e.g. Circadian oscillator has a period of oscillation on around 25 hours. Sensory input
 (e.g. dawn inhibits melatonin production by the suprachiasmatic nucleus), but the
 nest cycle still has the same period.

3) Patterned motor output generators are constructed by interconnedting nural elements
 in conventional inhibitory and excilatory circuits, with the added feature that some
 neurons must have an intrinsic burstiness in their firing pattern (oscillator neurons).

 The time constant of this intrinsic burstiness is an important contributor to the
 rhythm.Contrast, for example, the circadian oscillator at 25 hours with burster
 neurons which generate saccades (~10msec).

4) The circuits and intrinsic burstiness of (3), and therefore the motor tape, are under genetic control. Examples of this abound for invertebrates but there are not so many proven examples in vertebrates.
e.g. Tumble pigeons, Direct head scratching (i.e. under the humerus) performed by
 many non-passeriform bird families versus the indirect (i.e. over-wing) head-
 cratching pattern practised by many passerine birds.

4) Pattern generation can be triggered by brief activity of a single ëcommand neuroní or
 the action of a single ëcommand neurohormaoneí.

Neuromodulation allows different pattern generators to share the same neural
components.
e.g.a. anorexia nervosa and nucleus PV of hypothalamus; b.injection of some nueropeptides into the rat brain leads to stereotyped motor behaviour.

To see the Table of examples of motor principles (handed out in class) click here
 
 
 

Lecture 10:
Neuromodulation vs. Neurotransmission.          Chapter 17-1
 

Neuromodulators, Neurotransmitters and Dopamine

 Neurotransmission                                                                                                                   Neuromodulation
  (Inotropic Receptors)                                                                                                        ("Metabotropic"Receptors)
1. Ligand-dependent ion channels                                                                                   Receptors not linked directly to ion channels
 

a. GABA, glycine (inhibitory; open chloride                                                                            e.g. Serotonin 1c (chloride channel opened
 channels),                                                                                                                                indirectly via intracellular 2nd messenger),.
b.  kainate/quisqualate, nictonic, (excitatory;                                                                             DA receptor, opiate receptors, b adrenergic,
 open cationic channels)                                                                                                           muscarinic cholinergic
 

2. Specificity arises from synaptic location                                                                              Specificity arises from receptors
                                                                                                                                                (cf. endocrine system)
 

3. Small number of types (theoretically only                                                                            Great diversity of both receptors and ligands
 excitatory & inhibitory needed, but more in                                                                                  (neuropeptides, monoamines,)
 practice)
 

4. Ligand delivered directly to synaptic site                                                                              Ligand can diffuse to site of action
 

5. No change in intrinsic neuronal properties;                                                                          Alterations in intrinsic properties of neuron
 information transfer is between neurons                                                                                 (e.g. new channels exposed to alter intrinsic
 rather than properties of individual neurons.                                                                            burstiness than an alteration in  the signaling the                                                                                                                                               [vasopressin], coupling between neurons
                                                                                                                                                  [dopamine], modification of synaptic
                                                                                                                                                  proteins [muscarinic cholinergic],. Long
                                                                                                                                                   lasting inhibition [Serotonin 1c].
 

6. Brief action (1-100 msec)                                                                                                    Extended time course (minutes-hours ?years)
 

7. Action involves gating of ion channel                                                                                 Action involves intracellular secondmessengers
                                                                                                                                    e.g.1. Dopamine ......> G-protein.......>cAMP
                                                                                                                                                               ...............>    gap junction protein;
                                                                                                                                           2. Muscarinic Ach receptor  .........>  IP3
                                                                                                                                                     Protein   kinase C ........> synaptic protein
                                                                                                                                            3. Serotonin 1c.........> G protein .........>
                                                                                                                                               cAMP.. .......>A kinase...........> open chloride
                                                                                                                                                                                         channel
8. Effect limited to channels which are                                                                            Effect may involve a massive amplification of the
 bound by ligand                                                                                                             effect within cell (cf. Action of 1 photon to open
                                                                                                                                        millions of channels via G-protein second
                                                                                                                                        messenger system inside rod photoreceptor).
 
 
 

NEUROTRANSMISSION 1. Ligand-dependent ion channels    a. GABA, glycine (inhibitory; open chloride   channels),  b.  kainate/quisqualate, nictonic, (excitatory;   open cationic channels)    2. Specificity arises from synaptic location   (cf. endocrine system)   3. Small number of types (theoretically only   excitatory & inhibitory needed, but more in   practice)   4. Ligand delivered directly to synaptic site    5. No change in intrinsic neuronal properties;   information transfer is between neurons   rather properties of individual neurons.            6. Brief action (1-100 msec)    7. Action involves gating of ion channel                8. Effect limited to channels which are   bound by ligand	NEUROMODULATION 1. Receptors not linked directly to ion channels   e.g. Serotonin 1c (chloride channel opened indirectly via intracellular 2nd messenger),. DA receptor, opiate receptors, b adrenergic, muscarinic cholinergic   2. Specificity arises from receptors     3. Great diversity of both receptors and ligands (neuropeptides, monoamines,)     4. Ligand can diffuse to site of action   Alterations in intrinsic properties of neuron (e.g. new channels exposed to alter intrinsic burstiness than an alteration in the signaling  [vasopressin], coupling between neurons [dopamine, modification of synaptic proteins [muscarinic cholinergic],. Long lasting inhibition [Serotonin 1c].   5. Extended time course (minutes-hours ?years)   Action involves intracellular second messengers e.g. 1. Dopamine ......> G-protein......>cAMP .........> gap junction protein; 2. Muscarinic Ach receptor>>>>>>IP3>>>>>>>Protein kinase C >>>>>>>synaptic junctional protein); 3. Serotonin 1c >>>>>>>G protein Ë cAMP>>>>>>>>A kinase >>>>>>>>>chloride channels open   6. Effect may involve a massive amplification of the effect within cell (cf. Action of 1 photon to open millions of channels via G-protein second messenger system inside rod photoreceptor).

Lecture 11:
Neural basis of veterinary anaesthesia      Not in S&T. References to be added

Lecture 11: Veterinary Anaesthesia:

Triad of Anaesthesia:
A. Sleep
B. Muscle Relaxation
C. Analgesia
 

A. Hypnotics:
1. Increase GABAergic inhibition: Note complexity of the GABA receptor, whose effectiveness is increased by many molecules:- e.g.:-
 a. Barbiturates
 b. Benzodiazepines
 c. Steroidal anaesthetics
 d. Ethanol

Since hypnotics have no effect on nociception (some, e.g. barbiturates, even decrease pain threshold), they need to be supplemented with an analgesic if pain is present.

B. Muscle Relaxation:
1. Neuromuscular Blockade:
a. Short acting depolarization blockade. E.g. succynyl choline
b. long acting competitive N-M block  e.g. pancuronium chloride, gallamine triethiodide)
2. Xylazine
3. Benzodiazepines

C. Analgesia:

Pain vs. Nociception:
See PHYL2064 notes on pain and examples of nociception without pain, and of pain without nociception. www.uq.edu.au/nuq/jack/PHYL2064.html

Local Anaesthesia:
Xylocaine (and other procaine derivatives) act by blocking Na+ ion channels in nerve fibres.

a. Skin infiltration
b. Nerve Block
c. Digital Block
d. Limb block
e. Retrobulbar block
f. Epidural block
g. Spinal block
 

Note that local anesthesia (e.g. infiltration of the skin around the surgical incision) can be a useful adjunct to general anaesthesia, by reducing the dose and depth  of general anaesthesia needed.

This is an important consideration if the animal is fragile. Note that more men were killed by the new general anaesthetic, thiopentone sodium, than by bombs at Pearl Harbour, because it was not realized at the time that the usual dose for a healthy man was lethal for a hypotensive man suffering from blood loss and shock.
 

General Anaesthesia:
A. Short-acting barbiturates:
Thiopentone sodium
B. Steroidal Anaesthetics:
C. Inhalation
Halogenated hydrocarbons: halothane, isofluorane, chloroform.
 Interact with receptor proteins: show stereoisomer specifiity
Nitrous oxide
Cyclopropane
Ether

Neurolept Anaesthesia:

Ketamine hydrochloride is an NMDA receptor blocker that produces an altered state of consciousness with no change in sensory processing nor any suppression of reflexes. The preserved motor tone can interfere with some procedures, but there is no risk of aspiration pneumonitis so this is a suitable anaesthetic when you are on your own and have to be both anaesthetist and surgeon. The mode of action probably involves the ventral striatum, which is loaded with NMDA receptors and which normally acts to put the brain in an ìupî state by the release of dopamine.  NMDA receptors are involved in plasticity and are normally responsible for the dynamic organisation of self which is disturbed under ketamine (Yes, it is sharp and should hurt, but it is not happening to my body).
Desferrioxamine coma:
Small doses of NMDA receptor blocker in combination with the metal chelator, desferrioxamine, produce a coma that lasts for days, at doses where either alone has no effect. This is a mysteriously effective combination that Jack explains in terms of an effect on the ventral striatum, whose dopaminergic neurons are both very sensitive to NMDA receptor blockade and to blockade of energy-providing metalloenzymes like glutamine synthetase which reach very high concentrations in the very active neurons of the striatum.
 
 
 

Lecture 12:
Comparative neurology                             Not in S&T.

                                                      Bird - Mammal Comparison

                                                                Bird                                                            Mammal

Mitochondrion                              0.3% ROS/O2 transferred                                    3%ROS/O2 transferred

Lungs                                            Countercurrent                                                      Reciprocating bellows
                                                      Extract gas even at tiny levels                                Gas extraction ceases at alveolar equilibrium
                                                       e.g. miner's canary, gas anaesthesia
                                                     Air sac needs to be sealed off after craniotomy       No connection between air and bone
                                                     to prevent fungal infection in brain.

Iris and Ciliary Muscle                 Striated: Nicotinic receptors                                    Smooth: Muscarinic receptors
                                                     Atropine ineffective                                                 Atropine dilates pupil
                                                     Superfast accommodation: 10 Hz                            Slow accommodation: 1-2 Hz
                                                     Focus maintained during a fast dive                         Accommodation too slow to track fast changes
                                                     Iris responds to a strobe flash                                  No response to strobe

Retina                                           4 kinds of cone photoreceptor                                   2 or 3 kinds of cone photoreceptor
                                                      UV, blue, green, red                                                  Blue, green (red - primates)

Nucleus                                        very small (4 pg DNA)                                              large (9 pg DNA)

Sleep and Ageing                         Sleep less than same size mammal                             Sleep time proportional to metabolic rate
                                                     Live ~10X longer than mammal  of same size           Age inversely proportional to metabolic rate

Liver                                            Up-regulated P450 enzymes for phytotoxins            More sensitive to phytotoxins
                                                    e.g. emu metabolises ketamine 4X faster

Metabolism                                 20X increase in metabolic rate during                       1/20 peak metabolic activity  compared to birds
                                                    flight compared to running

Lecture 13:
Oscillatory avian saccadic eye movements.   Powerpoint Presentation of the Lecture

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