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ESSAY: 2006 BIOLOGY SCIENCE LECTURES "Brain Plasticity: From Molecules to Behavior

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author: BREZAN SIMON
Medical faculty Ljubljana, Institute of Clinical Neurophysiology, Slovenia

2006 Onassis foundation award- stipend Neuroscience summer school at FORTH institute: with Nobel E. Kandel etc. http://www.forth.gr/onassis/lectures/2006-07-17/index.html

August, 2006

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"The Molecular Logic of Long-Term Memory Storage" and "Animal Models of Mental Disorders" by Eric Kandel
#1 Any study of memory has to deal with 2 basic conceptual problems: first, the »system problem of memory», which is concerned with where in the brain are different types of memory stored and second, the »molecular problem of memory«, which covers electrochemical mechanisms about how is memory stored at each brain region. Organization of the brain can be modified by our experience and this contributes to the expression of biological individuality.The structure of human brain although with general framework provided by the genetic information, is nevertheless under continuous change by the electrical and molecular activity of the brain itself, including experience-dependent activity. »Paradox« of the evolution of the humans may be the selection of genes that allow the species to »escape« genetic determinism by endowing it with considerable plastic changes of brain architecture and ultimately human behavior. Therefore the structure of our brain is as much a result of our personal history and is not simply confined to predetermined, inflexible networks. When studying memory 2 complementary model systems can be used: molecular cell biology, for example for study of implicit memory (learned fear sensitization involving reflex pathways with only generalized arousal as a precondition) and methodologies of genetics, neural circuits or behavioural studies to approach explicit memory, for example space coding in hippocampus, with selective attention of research subjects or animals needed (may not be conscious as in humans). 2 main questions arise in long-term memory plasticity changes: what are mechanisms contributing to initiation of synapse-specific cell growth and what is the reason this changes can be sustained/maintained over time? The Aplysia provides good simplified model to study implicit memory changes: modifications of gill withdrawal reflex based on sensitization, habituation or conditioning of this defense reflex. There are fundamental molecular differences when comparing short-term (seconds/minutes) to long-term (days/weeks) mechanisms of this »memorized/learned« modifications. In each case, learning represents plastic changes in neural circuits as a function of number of environmental stimuli applied. Namely, in Aplysia stereotypical reflex circuit: siphon-sensory neuron-interneurons-motor neuron-gill modulatory control (tail shocks which result in 5HT (serotonin) input) induces learning/sensitization by altering the efficacy of the synaptic information transfer resulting in changes of the (post) synaptic potentials (facilitation/ depression). Basicly, short-term memory (STM) is mediated by only functional changes in electrical signalling between neurons, but long-term memory (LTM) requires activation of genes and even growth/maintenance of new synaptic connections. Literally, our brain changes anatomically when we remember something for longer time. For studying synaptic-specific plasticity microcultures of neurons with applications of 5HT pulses can be used. After this, synaptic-specific facilitation is observed by recording % EPSP- postsynaptic potential rise/changes compared to control. 2

Next important question is the nature of marking signal, which defines which specific synapses should be facilitated by capture of gene products (as LTM gene products are sent all over in the neuron from nucleus) and also, what is the nature of retrograde signals from modulatory synapses (site of initiation), which can induct the necessary LTM gene activation in the nucleus in the first place. STM sensitization is dependent of 5HT induced activation of adenylat cyclase (AC), which increases cAMP, which activates PKA protein in sensory neuron. PKA phosphorylates other target proteins (K+ and Ca2+ ion channels etc) which promotes depolarization, greater Ca2+ influx, so more of neurotransmitter (NT) can be mobilized and released to the motor neuron NMDA and AMPA receptors. This way EPSPs after sensory input remain raised compared to control even after modulatory input is not present anymore. For LTM to occur more 5HT pulses are needed. Then cAMP via PKA (synaptic marking), activated MAPK and CAMAP, importins (retrograde marker signals) proteins go to nucleus where they activate the transcription of early genes by means of activating CREB-1, CREB-2 inhibition (important inhibitory constraint, to allow just important things go to LTM), CBP and CRE transcription. This early genes products produce enzymes which activate PKA permanently (so LTM facilitation results) and also ortograde signals like kinesins, which deliver protein cargo coordinated to specific synapses and other factors to activate late phase LTM genes (CAAT). These are finally involved in stabilization of LTM: new synaptic growth and maintenance (BDNF, tPA…). Dilemma persists, whether this learning induced processes of synaptic growth are similar to »de novo« synaptic formation in developmental period with requirement of preformed presynaptic terminals. It seems both mechanisms can contribute to specific synapse formation, either activation of salient empty presynaptic ends or new synaptic growth. Important feature in maintenance phase of LTM seems to be local protein synthesis for synaptic marking, otherwise the grown synapses might retract (this happens with protein synthesis inhibitors). This also proves that LTM initiation and maintenance processes are two distinct, separate phases of the memory phenomena. CPEB protein bound with CPE has been found to play critical role in activation of dormant mRNA in synapses so this might be the regulation factor to maintain LTF and stabilize synaptic growth. In the beginning phase, it is upregulated by 5HT and this correlation is unlikely to be coincident. But what maintains the activity of CPEB when sensory signals are away? It might be that because it has properties of a prion, different from classical ones in the fact that it is regulated by physiological signals (5HT etc.) and that its active form is the self-perpetuative state of this new type of the prions. This features make him a good candidate for essential need for local protein synthesis to sustain LTM plasticity after the outer signal inputs are not present anymore. Space memory maps in hippocampus as example of explicit memory also share some common mechanisms of storage with the model described above (LTP resulting from presynaptic and postsynaptic mechanisms, Ca2+ influx through NMDA channels, then Ca2+/calmodulin kinase action, with cAMP, PKA activity, consequent changes in receptors, new proteins and retrograde signaling etc. involved). It also seems that dopamine released after specific focused attention has been paid to space location activates CPB-3 protein which might play the same role as CPEB described before- to stabilize the sensory maps by stabilizing the LTF in synapses as it has been shown to form prionic aggregates in yeast. So we might conclude, to a certain extent different types of memories share the same

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molecular mechanisms of memory storage initiation and maintenance processes. Both explicit and implicit memory storage also use modulatory transmitters besides main sensory input (5HT:bottom up or dopamine: top-down modulation from cortex to hippocampus) as salience signal and a CREB-mediated transcriptional switch for converting short-term to long-term memory. #2 Human molecular and genetic studies of mental disorders: genetic models in mice. Mental illnesses studies are limited by number of factors: little is known about anatomical basis, most of them are genetically complex and we know little about specific genes involved and their pathogenesis, but most important, it is very hard to construct satisfactory animal models for research of mind. Best exception is learned fear, which could predispose to anxiety, posttraumatic stress disorder, phobias and etc. Fear anatomy lies mainly in amygdala and it’s a very conserved pathway among species throughout phylogeny. Learned fear is produced by Pavlov conditioning combining a neutral (CS) with some noxious stimulus (US), so that eventually CS will produce fear response (autonomic, motor and behavioural signs) on its own. Conditioning represents a way where two environmental stimuli can be correlated in a way to learn to predict future events. LTP with pre- and postsynaptic changes (PKA etc.) could lead to learning here as well, as it can be blocked by blocking cAMP actions. Fear response may also be monitored by enhanced electrophysiological event-related potential recordings in brain regions involved. Candidate genes in mice models might serve as implication for humans too, for example in reducing fear learning. Knockout gastrin releasing peptide (GRP) receptor mice show strengthening of LTP in amygdala and fear response, because of loss of its inhibitory constraint in fear pathway. Instinctive fear seems to be independent of this mechanisms, so it is fundamentally different. Also, when animals are conditioned in a way where only the CS (tone) represents time of no danger, they will show relaxed “safety behaviour” (reduced fear) and LTD (long-term depression) in fear regions after that CS alone, also with safety responses with activation in striatum, prefrontal and cingulate cortex. This means they are not “forgetting fear” but “remembering safety” instead. The animals will actively show preference for a chamber with tone present. This poses challenges in the quest for the true nature of happiness. Is there universal molecular mechanism involved or, is happiness just the state of lack of fear? Is LTP/LTD by itself involved in switching the same tone from representing either fear or happiness? The animals will actually like the safety signal (tone alone), actively wanting to obtain this kind of CS. So there must be pleasure pathways and dopamine involved and increased activations had been recorded there. This represents the first evidence that pleasure patways are recruited by safety signals on their own. There are possibilities of new drugs development on basis of »safety learning» promotion with enhancing positive emotions (positive reinforcement of antidepressive drugs) in brain reward circuitry not just classically, by inhibiting fear pathways. Next, in schizophrenia, there is complex disturbance of emotional and cognitive functioning. We can search for endophenotypes to simplify the pathogenesis, which represent only the specific limited deficits of disease related to specific genes. Important finding in the disease is hypofunctional prefrontal cortex, where susceptibility gene for dopamine 2 receptor (D2R)

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has been identified. This defect results in increased occupancy and density of D2R in striatum and compensatory permanent decrease in D1 receptor pathways action. This is also the reason why blocking D2 R by antipsychotic drugs later in life does not improve cognitive function and negative symptoms, because compensatory changes in D1 R and resulting deficits (working memory, volition, attention etc.) had already been imprinted earlier in life. D2 R overexpresion thus seems to be responsible for deficits in WM in mice too. To conclude, in century of new biology of brain and mind, we should be able to detect anatomical and metabolic changes in brain and mental diseases and also to follow the results of drugs and psychotherapy (changes the way we consciously perceive the world, a lot of implicit effects). With genetical scientific progress also different approaches for different subtypes of diseases and individuals should be successfully put into life.

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"Building Neural Representations of Habits " and "Extreme Habits: Toward Molecular Mechanisms" by Ann Graybiel
#1 Neurological and neuropsychiatric diseases, like Parkinson's disease, Huntington's disease, dystonia, obsessive-compulsive disorders, depression or even schizophrenia all include some type of basal ganglia pathology in their complex pathogenesis. Recently it has become clear that basal ganglia (BG) disorders don't produce just motor symptoms and signs but evidently also cognitive deficit. Why is there such important role of BG in complex brain functions? Probably because BG have important reciprocal connections with frontal cortex, so called cortico-basal ganglia projection loops which are critical for different types of goal-directed behaviour by selection of different actions. This feedback neural circuits include neocortex- via glutamate to BG- Pallidum and S. Nigra and back to cortex again. When reward is presented, reward (pleasure) systems of the brain join into the circuit as well and dopamin is released via S. nigra to reinforce the behaviour produced by the loop. This way, when such cycles repeat many times, this results in loop facilitation and specific type of behaviour reinforcement. This probably makes the basis of our habits or similarly, addictive stereotypic behaviours also generally. In animal models, habits can be studied by habit learning in T-maze task for example. Single neuron recording and neuron population tuning show time shifts of activity with respect to different phases of learning and parts of a task. Task-selectivity of striatal neuron ensembles changes during aquisition af task and is dinamically tuned, with firing rates reprogrammed during learning or unlearning the habits. Entropy of striatal projection acitivity decreases in learning, we can observe start related neurons population, cue related, decision related etc. Non-task responsive neurons seem to put noise away. Habits or action can be seen from action chunking perspective, where the habit/action/behaviour is broken into distinct smaller sequences/episodes based on stimulus-response movement learning (S-R). Reinforcement learning can also be modeled in computational agent-environment (reward)-value function models. Attractor state models predict that BG help to set the attractor state of action patterns in the cortex. It has been also shown that during learning sequences theta band LFP electrical oscillations appear in striatum not just in hippocampus simultaneously and they are strongly synchronized- theta coherence increases as task related response. Coherence phase changes during learning also and coherence peaks at choise period. All this may reflect that cross-systems interactions (striatum- hippocampus, striatum- cortex) are needed during learning. They could be mediated by synchronized oscillations. In monkeys it has been shown that caudate nucleus activity extra peaks also after last eye-movement and is not related to reward, so probably BG can produce some kind of task end-signal to stop certain sequence/activity before frontal cortex. So in contrast to »delay period activity« in PFC (prefrontal cortex), in striatum we seem to get »end-period activity« and different dillemas persist of their interaction and frequency correlations.

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So this shows in the brain there is no single »teacher«, but behaviour and habits result from interactions of thalamocortical planner circuits, BG loops with reward centers (D, 5HT modulation) involved and of course with inputs from »cortical« intentions, evaluation, context, memory and sensory-motor stimuli. All this produces cognitive pattern generators with resulting cognitive actions. #2 For extreme habits, by using e.g. deep brain stimulation (DBS), it has also been shown that cortico-BG loops play a role in selection processes of different behaviour patterns, encoding even parts of romantic love attachment, reward, trust and altruistic punishment behaviour in humans. This can be accomplished by BG targetting of executive loops of sensory-motor, associative and limbic (reward centers) cortex. Interneurons and inhibitory networks play most important role in cortex and BG because of their possible combinatorial activitycombinations for selecting variety of behaviour patterns. But the input to striatum has to be relatively strong to produce overthreshold responses. Nevertheless, striatum has also a rich subtreshold activity, which might be also important as their modulation can have different effects on the final responses/outputs. Important question is how habits can become uncontrollable, like obssesive-complusive disorder (OCD) and other addictive habits? Is there a common ground with drug addiction? It proves out that drugs, addictive habits all end up activating common final reward pathways where dopamin signaling is increased. OCD regions more active then in control are the same as drug addiction activated regions (striatum, orbitofrontal cortex, ant. cingulate). There is a lot to be modulated by D1 and D2 receptors and serotonin in striatum with plastic changes (LTP/LTD) in synapses. Striosomes (»systems of striatum«) and Ras superfamily proteins, have been shown to be strongly expressed in BG and are related to addiction and learning, memory. In addictive habits, there is increased sensitization to drugs and rewards- this can lead to increased LTPs in the neural circuits producing repetitive stereotypic behaviour. Serotonin lowers that, so this is the reason why antidepressive drugs might be useful in treating OCD. Defects result from altered gene expression with modifications of different neurotransmitters roles in modulatory sensitization etc. Knockout models have shown that modifications of this molecules action can lower the sensitization to stereotipy induced by amphetamin dosage only but not to other types of sensitization and learning. This way we approach the molecular view of extreme habits and their possible treatment strategies.

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"Developmental Plasticity across the senses: learning to match sound and vision " by Irini Skaliora
Plasticity is ability of brain to change as a result of experience/environmental stimuli. It can be defined at any level of brain organization and it can serve a positive adaptive purpose (development, adult learning…) or maladaptive in rare occasions (phantom pain, addictions, traumas…). Also the studying of plasticity can be therefore done at different levels. Developmental plasticity is a distinct, heightened sensitivity form of plasticity in nervous systems with a critical time periods involved during ontogeny. It has characteristical qualitative and long lasting consequences on future behavioural repertoire of organism. Development of nervous system starts with neurogenesis, then migration follows, axonal extensioning and target identification with synaptogenesis. Then morphological and functional differentiation takes place.The major role in the earlier processes is being played by genetic and epigenetic mechanisms which are intrinsic to embryo and based on activity of nervous system itself. In model studies we use systems where all this intrinsic influences are being minimized so we can observe changes as a function of stimuli input. In superior colliculus (SC) there is convergence of auditory and visual input and output is represented by orienting movements by motor systems. SC contains spatial sensory maps aligned to each other as a multimodal processing area with advantages of all sensory systems convergence to same motor pathways with goal- directed orienting responses and associated with same target in space. There is also advantage of increasing salience of multisensory interactions by favouring crossmodal stimuli associated with common source. How are the sensory maps formed and maintained? Visual system map is present even before birth and is leading other to align. Auditory system maps based on different characteristics of auditory stimuli are being aligned through the process of learning where normal visual and auditory experience is required over prolonged period. In critical period if something goes wrong because of plasticity there can be still aligning correctly. Possible sites of plasticity probably involve SC layer. If we remove parts of visual layers then auditory map gets srambled up. Auditory and visual maps remain intact in sides not affected by manipulation. So vision seems to calibrate auditory map spatial tuning. This is based on anatomical (spatially selective monosynaptic inputs even before birth etc.) and functional connectivity between different sensory modes and activity-dependent sinaptic integration processes (facilitation of visual and auditory input and temporal independence of inputs). Hypothesis is that synaptic inputs from superficial SC on to deep SC neurons are controlling the efficacy of auditory synaptic inputs on to the same neurons by activity-dependent mechanisms. So these circuits are the likely site of experience-dependent plasticity. Early experience seems to leave a permanent »trace of learning« like proved in owls and later plasticity is restricted to in critical period previously learned associations. Dilemmas persist also about differences between developmental vs. adult plasticity generally.

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"Neural encoding and decoding: multidisciplinary studies and mechanisms of serial order and memory scanning" by Apostolos Georgopoulos
Methods of investigation of brain as computational cognitive system can be divided into: experimental psychology, which studies behavioural capacities and puts up hypotheses on the nature of the human mental processes; electrophysiological methods (EEG, ERP) with high time resolution of multielectrode recordings of brain fine grain electrical activity, where coding of information resides in small ensembles of cells; magnetoencephalography (MEG), where dynamic interactions among neural networks from whole brain can be detected and used for exploring encoding/decoding processes; fMRI, where localization of brain activity during tasks can be defined or functional connectivity estimated and finally, artificial neural networks (ANN) modelling for generating new ideas, hypotheses across species to find common mechanisms of brain function. Neural en-coding of information represents systematic variation of neural activitay with respect to a behavioural variable (e.g., stimulus-response function). Known research options are single cell recordings and standard statistic is used. On the other hand, just the opposite, neural de-coding refers to extracting the value of variable from the neural activity, which makes it possible to predict behaviour. Extracted data are from neuronal populations clasically and multivariant statistics is being used to study population vectors (NPV) for continuous variables or discriminant analysis for discrete variables. The synaptic connections in brain networks play a very important role because their specific organization in a given brain area determines a specific function performed by that area. Researchers develop large-scale mathematical models of the brain network and then explicitly simulate these models using high-performance supercomputers. The current research should be important for developing new generation of neural prosthetics (brain- computer interface) that are driven by brain signals to assist, for example, paralyzed patients or amputees. Particularly, simulations of large-scale brain models could be important for detecting the relevant brain signals and their spatial localization and temporal dynamics. In motor systems, the study of direction coding shows that encoding is based on directional tuning of neurons (different neurons show distinct firing action potential rates with respect to direction angle- they have »preferred directions«) for movement, but decoding reveals population tuning vectors which can be used for neural control of artificial neural prostheses to move specific devices. From summated neural vectors you can further on calculate the population vector in multidimensional space to control/predict specific trajectory/limb control or space/location as neural activity precedes the movement. Time-varying population vectors can be observed in instructed-delay or memorized-delay tasks where there is increase in their activity even in primary motor cortex not just prefrontal one. During reaction time there are rotations of population vectors (NPV) according to demands of the motor task. But in memory serial recall tasks you have a switch abrupt activity to different NPV vectors according to the serial position in a sequence without any spatial component included, so memory and motor processes are coded differently to a certain extent .

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From MEG or EEG data signal carries sufficient trajectory info to predict/decode movement trajectory or even higher mental and musical imagery (for example, Pink panther, Bach song) from these noninvasive recordings alone. So information is present in a signal, but how extract it? MEG from whole brain signals shows overlapping but still distinct, different dynamics for different tasks. Coherence, cross-correlation function (CCF) between pre-whitened data adds to this studies by exploring the interactions among neuronal populations, which are also proven to be distorted in pathological states of the brain. CCF, partial correlation and linear discriminant analysis can reveal differentiation between different diseases just on a basis of analysis of simple fixation task. This means that already resting state brain networks are specifically synchronized (more general increases compared to focused taskrelated increases), this is regulated somehow and gets disrupted in disease. Next, in studying memory, serial order neural mechanisms are very important as everything in time is serially ordered and all processes are meaningful only in time context of serial sets: the stream of thoughts, the flow of conscioussness, memory or integrative action, speech etc. Serially ordered units are also called chunks. Is temporal indexing absolute or relative? There is no anatomical absolute clock in the brain so research shows it is relative. In context-recall serial position memory scanning tasks (during reaction time) it has been proved that cca. 20% of all brain cells activated during specific task encode just the specific serial positions of stimuli, the others encode direction, force etc. By decoding these vectors we can find the error rate is lowest for first and last positions so primacy and recency effects allso have to be accounted for in neural activity somehow. In single cell recordings we can reveal that certain % of cells specifically activates/fires as a function of serial position which is shown in frequency of its action potential firing rate, but others fire only with respect to specific segment, shape, length parametres etc. Parallel co-processing of more parametres is needed, as we use serial order movements to construct, redraw a certain shape for example. How to decode a specific segment? Estimations of internal neural representations show separated strengths of serial order position activity after the shape was shown and this separation of different population activites starts before and is prolonged to the redrawing/copying period of shape also, with separate distinct peaks of firing of different involved neural ensembles for different time points/positions in the sequence/series.

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"Vocal Ontogeny in Songbirds: Models for Vocal Learning" and "Neuronal Replacement in Adult Brain and its Possible Relation to Learning" by Fernando Nottebohm
The biology of vocal learning in birds has to focus on origins of vocal learning, where crucial steps are: auditory memory followed by motor matching. The kinds of information that are conveyed with singing could be individual identity, community membership, health and affluence. From neuroanatomy view, birds use a special organ for singing and also special brain circuits and specialized centers to produce it. There is a sensitive period for learning which is commonly based on two strategies: imitation and improvisation. Learning complements an innate, flexible program for vocal ontogeny. Song system consists of musculature, module that tells it what to do, learning aquisition system not for production and auditory information module. These seem to be equally represented in both sides of bird brain. Canaries are more opened learners but Zebra finch have distinct sensitive period. To learn birds use either repetition strategy where each of the repeated segments changes serially in time or motif strategy where they try to match everything immediately. When learning song for female partners there also endocrine changes appear and outer look changes. Interestingly, at young canaries testosteron treatment induces highly structured change into adult type of song only with 8 syllables they know. »Phrases« of these songs contain repetition of syllables. In chipping sparrow birds they are distinct male and female song patterns ment for food begging, male have more dynamic complex patterns but can change to female songs. Birds use precursor songs to make a real song later and imitate a tutor song, then later they choose which it is most alike and quickly modify it to the tutor song. This shows the meaning of plastic adaptation in learning. In biology of neuronal replacement during learning, questions arise why are some neurons replacable and others not? What is the relationship between number of neurons in vocal centers and song repertoire? Female have smaller one and they do not sing, there is a sexual dimorphism, but also it seem that always when number of neurons decreases there is drop of repertoire eventhoug this happens rarely also when neurons increase. Vocal centers neuro- and synaptogenesis also changes with seasons or testosterone dosage which is another proof of plasticity. It arrises from neurogenesis in ventricles and stem cells can migrate to vocal centers and also changes in other neocortex are observed. When there is peak in neuronal death and recruitment there is also peak in syllables amount in songs. BDNF factor seems to play a critical role in amount of neuronal survival which is related to amount of singing.This survival is conditioned by vacancies. Singing patterns can be restored after laser lesioning even but only if auditory guidance is present in non-deaf birds. It is not known if birds build new templates from the beginning or use old neurons that remained. Interesting general question remains why some neurons are replaceable and others are not? Or why do we need replacement of neurons at all if we have efficient synaptic plasticity for LTP etc. which function well?

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Maybe there is a trade-off between replaceable neurons and non replaceable neurons in a way that there is a trade off between knowing and acquiring new memories information. Or it may be that we need replacement as a final means to erase long-term memories which might represent the last step in differentiation which is irreversible. On the other hand, neuronal replacement could counteract number of brain diseases where neurons are lost but this mechanism is not very efficient in humans, except hippocampus. Maybe it is even more important to preserve the important memories by freezing synaptic efficacy at many places after all.

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"The Multiplicative Neuron" by Panayiota Poirazi
#1 Mnemonic capacity of a neuron means that is is able to learn, store and recall information. Computational neuroscience should provide means to reveal how a neuron can encode and decode information. What is the smallest computational level? Where and how are the memories stored? Hebb (LTP/LTD based on the fact that “neurons that fire together also wire together” by increasing efficacy of synaptic transfer) provided a model in which the overall capacity to store memories and learning depends on the amount and strength (weights) of the synapses in a neural connection pattern, where their location doesn’t matter and the synaptic weights just summate linearly because postsynaptic neuron is a single computational unit here. However, by studying signal integration at a single neuron level, the rewiring hypothesis seems to provide a better model, because it can account for structural plasticity (formation/elimination of synapses during learning), fast changes in synaptic strength (recent memories can be erased) and non-linear dendritic events, which are not detected at cell body. The rewiring hypothesis takes into account both the strength of the synapses and their location and recent evidence supports this alternative view. The neuron simulation model found that between branches signaling is linear, but within branches (2 inputs on the same dendrite) it is supralinear. So the neuron behaves as a twolayer neural network, which gives it more capacity to learn. This means that indeed the synapse distribution affects neuronal output/firing rate; the same kind of synapses active, but with a different distribution could lead to differences in the output. So the smallest computational level seems not to be the neuron, but the synapse, dendrite or even smaller parts of a dendrites. In this way if a dendrite is a single computational unit (individually thresholded dendrites in a neuron), a wiring change is functionally distinct from Hebbian weight change and brings new extra level of computation and increasing the storage capacity of these cells. #2 Molecular mechanisms of declarative explicit memory : working memory seems to be mediated by involvement of hippocampus also, not just the prefronto-posterior brain networks. CA1 cells of the hippocampus show in vivo persistent delay period activity during WM task. What are the biophysical mechanisms that underlie this persistent activity and WM? Delay period activity is calcium dependent: L-type Ca2+ channels show influx after stimuli with role of AcH or NMDA receptors. Next, modulation of neuronal excitability could provide an alternative learning and memory mechanism. It can be achieved by intrinsic mechanisms: timing between EPSP and backward AP in 2 neurons for control of the initiation and timing of LTP vs. LTD or broadening of AP signal which produces the short ehancement of synaptic transmission.

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It is known that there is a decrease of excitability of this neurons with age. This decrease is accompanied by an increase in calcium influx, an increase in the afterhyperpolarization (AHP) current and a decrease in the removal of calcium from the cell. But in contrast, afterdepolarization (ADP) is needed for working memory in accordance with Lisman Idiart Jensen working memory model. In a model of the CA1 cell, it was found that the aged cell show a plateau of dendritic potentials. By decreasing the influence of the L-type calcium channels, or the AHP current, there is a restoration of the sustained delay period activity. This may have therapeutic consequences to boost up the memory system in aged population and disease. Also it has been proved that neuronal output is dependent on timing characteristics of input in a way that small interstimulus intervals (ISI) enhance excitability and can switch cells to the bursting mode. But other ISI can lead to blocking of spiking/firing. Synaptic clustering enhances neuronal excitability and dampens spike blocking induced by PP stimulation. This stimulation acts as a temporal switch which modulates the response from enhancement to suppression.That way CA1 hippocampus cells could also function as familiarity detectors by comparing old/retrieved (CA3) experiencies and current memories (PP) by different response based on different ISI input.

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"Human Sensory-Motor Adaptation to Non-terrestrial Force Environments" by James Lackner

What is the relationship and difference between extra-terrestrial nervous system plasticity and plasticity on earth? Is extra-terrestrial plasticity "natural" ? Because in space according to little weight load, muscle and bone atrophy arise, the working of muscles and body sensory cortical maps will change, first foot areas and premotor cortex. Artificial gravity is being exploited for long space flights training. This artificial gravity should be generated by a rotating space shuttle which produces centrifugal force on subjects. Rotation and sense of movement with respect to gravity are produced in different vestibular system of the inner ear. People have to adapt to the rotation: you become heavier or lighter in walking in opposite directions. Bending becomes heavier too, and tilting your arms upwards becomes lighter. Also oculomotor control responses have to be adapted. Because of the rotation, Coriolis forces are generated. These forces become important when you want to move, e.g. they will deviate the pathway of moving your arm straightforward. The Coriolis forces will become larger (and thus more influential) when rotation is faster. Surprisingly enough, people can adapt to these forces very well. It was discovered that also during normal life on Earth there is continuous recallibration. Coriolis forces on Earth are generated by a turn-and-reach combination. The most important actors in recallibration are muscle spindles. Muscle spindles are the intrafusal muscle fibers in alpha-motorneurons and their sensitivity and feedback can be easily adjusted. The Coriolis forces act also on the head vestibular system as an inertial mass. With low G-levels, bending down feels and looks like as if the floor goes down. Coming up again raises the feeling/illusion that the floor goes up too. At high G-levels the pattern is exactly the opposite. The level of activity of the alpha-motorneurons is too high at the higher G-levels, but after a while the levels will adapt in a process of recallibration. Recallibration can thus be seen as an automatic, "natural" process, which demands basicly similar plasticity processes either in Earth or in “outer” Universe, based on inner brain maps of our bodies and outer environment.

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