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When mapping the different neural pathways in the brain, often pictures such as these are drawn:
Or similar versions. Clearly these sketches draw the neural pathways as being a two-sided connection, as can be judged from the double arrows. I was wondering, how such bidirectional pathways work. Specifically, I am interested to know whether individual neurons constitute such a bidirectional pathway between different parts of the brain, or if the bidirectional pathway can be thought of as a 'circuit': a pathway of neurons that eventually comes back to a certain part of the brain.
This question is especially interesting in light of abstract thoughts. Let's make some extremely generalising (and ludicrous) assumptions and assume that our conscious thoughts are governed by our hippocampus only. That is, we assume that thinking about a matter without input from sensory neurons causes the hippocampus to fire an action potential into some specific cluster of neurons (somewhere in the brain). E.g. we assume that thinking about the letter 'A' causes the hippocampus to fire an action potential into the cluster of neurons that represents the letter 'A'. Let's also assume that the memory we have regarding the letter 'A' must be returned to the hippocampus, in order to continue our thought process. For example, I might want to recite the alphabet in my head. Starting with the letter 'A', I then continue to the letter 'B', which arises in my conscious thoughts as a result of the firing of the cluster of neurons that contain information regarding the letter 'B'.
So if we assume the circuit, conscious thoughts $ ightarrow$ cluster of information fires $ ightarrow$ conscious thoughts to exist, then how would its feedback most likely work?
Let's take the example where we think of the letter 'A' and want to think of the letter 'B'. I have sketched two different theories about how the communication between these two clusters of information and the 'governing body of thoughts' (which I assumed to be the hippocampus), might be:
The difference is the following: in the second theory, all individual neurons are expected to be able to communicate directly to the hippocampus. Whereas in the first theory, the feedback to the hippocampus arises only when we have reached our destination: the letter 'B'. Clearly, if we assume that a specific thought process is able to self-induce action potentials (of course, this is highly debatable), at least one of the two theories must be partially true. For which one exists evidence?
My first intuition would be to say that the first theory is more likely, but this is ambiguous under Dale's principle: why would only some cells be connected to the hippocampus? On the other hand, I found it hard to believe that every individual neuron is directly connected to the hippocampus.
So now that I have explained my thought process, my question can be formulated as follows:
How are clusters of neurons that are involved in abstract thoughts bidirectionally connected to the thought-governing-body (whichever actual part(s) of the brain this is)? Can we say that just a single neuron in the cluster provides the feedback to the thought-governing-body, or is every individual neuron that is involved in conscious thought potentially capable of a feedback loop?
Disclaimer: Yes, I'm not up-to-date to all the latest advances in neuroscience. Yes, I'm aware that my question might be ambiguous with respect to all the different types of neurons, connections and theory about neuronal networks and micronetworks. My question, however, is concerning the likelihood of the theories I presented. For which one do we have evidence. Are both wrong? If so, in what way? Are both right? If so, when does their difference play a role? etc.
To give a simple answer to the first part, the feedback generally happens in circuits of at least two neurons. A synapse is generally one way, transmitting information from the presynaptic neuron's axon to the postsynaptic neuron's dendrite. I'm sure there's caveats and exceptions because biology always has that, but that's the norm. A simple feedback loop might look like this: A excites B which excites C. C inhibits A as negative feedback.
The second question relies pretty heavily on the assumption that conscious thought originates from a particular part of the brain, or that one neuron is dedicated to one concept. This doesn't seem to be true. Things like memory and thought appear to be distributed, emergent properties of several circuits and areas. They might be organized or integrated by a particular part of the brain but it's not the same as having one central executive looking at all the inputs deciding what you think.
Think of it like a person working on an Excel spreadsheet. There's all the code for the OS, the software, the formulas in the spreadsheet. Those are all important parts of the process but the user doesn't need to see any of that. All they need to see is the end products of each process, and then they can figure out what to do with those products. So circuits and neurons can be involved in lower processing without connecting directly to the area that organizes and integrates information. Also, because higher level processes like thought are so distributed, there's likely to be multiple centers organizing/integrating information and all giving feedback to each other. Does that make sense?
Side note: I think you might be misunderstanding Dale's principle. When it says that neurons have the same chemical action at every synapse, that means they release the same neurotransmitter(s) but that doesn't mean they have to be connected the same way or that the neurotransmitter release has the same results. For example, say a neuron releases the excitatory neurotransmitter glutamate. If it synapses on another neuron that releases glutamate, that will promote excitation. But if it synapses on an inhibitory neuron that releases GABA, then exciting that neuron will actually result in inhibition.
On a late summer day in 1953, a young man who would soon be known as patient H.M. underwent experimental surgery. In an attempt to treat his debilitating seizures, a surgeon removed portions of his brain, including part of a structure called the hippocampus. The seizures stopped.
Unfortunately, for patient H.M., so too did time. When he woke up after surgery, he could no longer form new long-term memories, despite retaining normal cognitive abilities, language and short-term working memory. Patient H.M.’s condition ultimately revealed that the brain’s ability to create long-term memories is a distinct process that depends on the hippocampus.
Scientists had discovered where memories are made. But how they are made remained unknown.
Now, neuroscientists at Harvard Medical School (HMS) have taken a decisive step in the quest to understand the biology of long-term memory and find ways to intervene when memory deficits occur with age or disease.
Reporting in Lynn Yap, HMS graduate student in neurobiology, and Michael Greenberg, chair of neurobiology in the Blavatnik Institute at HMS.
“Memory is essential to all aspects of human existence. The question of how we encode memories that last a lifetime is a fundamental one, and our study gets to the very heart of this phenomenon,” said Greenberg, the HMS Nathan Marsh Pusey Professor of Neurobiology and study corresponding author.
The researchers observed that new experiences activate sparse populations of neurons in the hippocampus that express two genes, Fos and Scg2. These genes allow neurons to fine-tune inputs from so-called inhibitory interneurons, cells that dampen neuronal excitation. In this way, small groups of disparate neurons may form persistent networks with coordinated activity in response to an experience.
“This mechanism likely allows neurons to better talk to each other so that the next time a memory needs to be recalled, the neurons fire more synchronously,” Yap said. “We think coincident activation of this Fos-mediated circuit is potentially a necessary feature for memory consolidation, for example, during sleep, and also memory recall in the brain.”
The vertebrate central nervous system (CNS) is derived from the ectoderm—the outermost germ layer of the embryo. A part of the dorsal ectoderm becomes specified to neural ectoderm – neuroectoderm that forms the neural plate along the dorsal side of the embryo.  This is a part of the early patterning of the embryo (including the invertebrate embryo) that also establishes an anterior-posterior axis.  The neural plate is the source of the majority of neurons and glial cells of the CNS. The neural groove forms along the long axis of the neural plate, and the neural plate folds to give rise to the neural tube.  When the tube is closed at both ends it is filled with embryonic cerebrospinal fluid.  As the embryo develops, the anterior part of the neural tube expands and forms three primary brain vesicles, which become the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon). These simple, early vesicles enlarge and further divide into the telencephalon (future cerebral cortex and basal ganglia), diencephalon (future thalamus and hypothalamus), mesencephalon (future colliculi), metencephalon (future pons and cerebellum), and myelencephalon (future medulla).  The CSF-filled central chamber is continuous from the telencephalon to the central canal of the spinal cord, and constitutes the developing ventricular system of the CNS. Embryonic cerebrospinal fluid differs from that formed in later developmental stages, and from adult CSF it influences the behavior of neural precursors.  Because the neural tube gives rise to the brain and spinal cord any mutations at this stage in development can lead to fatal deformities like anencephaly or lifelong disabilities like spina bifida. During this time, the walls of the neural tube contain neural stem cells, which drive brain growth as they divide many times. Gradually some of the cells stop dividing and differentiate into neurons and glial cells, which are the main cellular components of the CNS. The newly generated neurons migrate to different parts of the developing brain to self-organize into different brain structures. Once the neurons have reached their regional positions, they extend axons and dendrites, which allow them to communicate with other neurons via synapses. Synaptic communication between neurons leads to the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior. 
Some landmarks of neural development include the birth and differentiation of neurons from stem cell precursors, the migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons and dendrites from neurons, guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes in synapses, which are thought to underlie learning and memory.
Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and activity-dependent mechanisms. Activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic programs played out within individual neurons. These include differentiation, migration and axon guidance to their initial target areas. These processes are thought of as being independent of neural activity and sensory experience. Once axons reach their target areas, activity-dependent mechanisms come into play. Although synapse formation is an activity-independent event, modification of synapses and synapse elimination requires neural activity.
Developmental neuroscience uses a variety of animal models including the mouse Mus musculus, the fruit fly Drosophila melanogaster, the zebrafish Danio rerio, the frog Xenopus laevis, and the roundworm Caenorhabditis elegans.
Myelination, formation of the lipid myelin sheath around neuronal axons, is a process that is essential for normal brain function. The myelin sheath provides insulation for the nerve impulse when communicating between neural systems. Without it, the impulse would be disrupted and the signal would not reach its target, thus impairing normal functioning. Because so much of brain development occurs in the prenatal stage and infancy, it is crucial that myelination, along with cortical development occur properly. Magnetic resonance imaging (MRI) is a non-invasive technique used to investigate myelination and cortical maturation (the cortex is the outer layer of the brain composed of gray matter). Rather than showing the actual myelin, the MRI picks up on the myelin water fraction, a measure of myelin content. Multicomponent relaxometry (MCR) allow visualization and quantification of myelin content. MCR is also useful for tracking white matter maturation, which plays an important role in cognitive development. It has been discovered that in infancy, myelination occurs in a caudal–cranial, posterior-to-anterior pattern. Because there is little evidence of a relationship between myelination and cortical thickness, it was revealed that cortical thickness is independent of white matter. This allows various aspects of the brain to grow simultaneously, leading to a more fully developed brain. 
During early embryonic development of the vertebrate, the dorsal ectoderm becomes specified to give rise to the epidermis and the nervous system a part of the dorsal ectoderm becomes specified to neural ectoderm to form the neural plate which gives rise to the nervous system.   The conversion of undifferentiated ectoderm to neuroectoderm requires signals from the mesoderm. At the onset of gastrulation presumptive mesodermal cells move through the dorsal blastopore lip and form a layer of mesoderm in between the endoderm and the ectoderm. Mesodermal cells migrate along the dorsal midline to give rise to the notochord that develops into the vertebral column. Neuroectoderm overlying the notochord develops into the neural plate in response to a diffusible signal produced by the notochord. The remainder of the ectoderm gives rise to the epidermis. The ability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction.
In the early embryo, the neural plate folds outwards to form the neural groove. Beginning in the future neck region, the neural folds of this groove close to create the neural tube. The formation of the neural tube from the ectoderm is called neurulation. The ventral part of the neural tube is called the basal plate the dorsal part is called the alar plate. The hollow interior is called the neural canal, and the open ends of the neural tube, called the neuropores, close off. 
A transplanted blastopore lip can convert ectoderm into neural tissue and is said to have an inductive effect. Neural inducers are molecules that can induce the expression of neural genes in ectoderm explants without inducing mesodermal genes as well. Neural induction is often studied in Xenopus embryos since they have a simple body plan and there are good markers to distinguish between neural and non-neural tissue. Examples of neural inducers are the molecules noggin and chordin.
When embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neural differentiation (express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. In explant cultures (which allow direct cell-cell interactions) the same cells differentiate into epidermis. This is due to the action of BMP4 (a TGF-β family protein) that induces ectodermal cultures to differentiate into epidermis. During neural induction, noggin and chordin are produced by the dorsal mesoderm (notochord) and diffuse into the overlying ectoderm to inhibit the activity of BMP4. This inhibition of BMP4 causes the cells to differentiate into neural cells. Inhibition of TGF-β and BMP (bone morphogenetic protein) signaling can efficiently induce neural tissue from pluripotent stem cells. 
In a later stage of development the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon, at the mesencephalic flexure or cephalic flexure. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).
The alar plate of the prosencephalon expands to form the telencephalon which gives rise to the cerebral hemispheres, whilst its basal plate becomes the diencephalon. The optical vesicle (which eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon.
In chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specific environmental conditions - different concentrations of signaling molecules
Dorsoventral axis Edit
The ventral half of the neural plate is controlled by the notochord, which acts as the 'organiser'. The dorsal half is controlled by the ectoderm plate, which flanks either side of the neural plate. 
Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells of ectoderm, which go on to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked by the organiser. The organiser may produce molecules such as follistatin, noggin and chordin that inhibit BMPs.
The ventral neural tube is patterned by sonic hedgehog (Shh) from the notochord, which acts as the inducing tissue. Notochord-derived Shh signals to the floor plate, and induces Shh expression in the floor plate. Floor plate-derived Shh subsequently signals to other cells in the neural tube, and is essential for proper specification of ventral neuron progenitor domains. Loss of Shh from the notochord and/or floor plate prevents proper specification of these progenitor domains. Shh binds Patched1, relieving Patched-mediated inhibition of Smoothened, leading to activation of the Gli family of transcription factors (GLI1, GLI2, and GLI3).
In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At low concentrations it forms ventral interneurons, at higher concentrations it induces motor neuron development, and at highest concentrations it induces floor plate differentiation. Failure of Shh-modulated differentiation causes holoprosencephaly.
The dorsal neural tube is patterned by BMPs from the epidermal ectoderm flanking the neural plate. These induce sensory interneurons by activating Sr/Thr kinases and altering SMAD transcription factor levels.
Rostrocaudal (Anteroposterior) axis Edit
Signals that control anteroposterior neural development include FGF and retinoic acid, which act in the hindbrain and spinal cord.  The hindbrain, for example, is patterned by Hox genes, which are expressed in overlapping domains along the anteroposterior axis under the control of retinoic acid. The 3′ (3 prime end) genes in the Hox cluster are induced by retinoic acid in the hindbrain, whereas the 5′ (5 prime end) Hox genes are not induced by retinoic acid and are expressed more posteriorly in the spinal cord. Hoxb-1 is expressed in rhombomere 4 and gives rise to the facial nerve. Without this Hoxb-1 expression, a nerve similar to the trigeminal nerve arises.
Neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. Neurons are 'post-mitotic', meaning that they will never divide again for the lifetime of the organism. 
Epigenetic modifications play a key role in regulating gene expression in differentiating neural stem cells and are critical for cell fate determination in the developing and adult mammalian brain. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation.   DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several sequential steps by TET enzymes that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the DNA base excision repair (BER) pathway. 
Neuronal migration is the method by which neurons travel from their origin or birthplace to their final position in the brain. There are several ways they can do this, e.g. by radial migration or tangential migration. Sequences of radial migration (also known as glial guidance) and somal translocation have been captured by time-lapse microscopy. 
Radial migration Edit
Neuronal precursor cells proliferate in the ventricular zone of the developing neocortex, where the principal neural stem cell is the radial glial cell. The first postmitotic cells must leave the stem cell niche and migrate outward to form the preplate, which is destined to become Cajal-Retzius cells and subplate neurons. These cells do so by somal translocation. Neurons migrating with this mode of locomotion are bipolar and attach the leading edge of the process to the pia. The soma is then transported to the pial surface by nucleokinesis, a process by which a microtubule "cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its final destination.  Radial glial cells, whose fibers serve as a scaffolding for migrating cells and a means of radial communication mediated by calcium dynamic activity,   act as the main excitatory neuronal stem cell of the cerebral cortex   or translocate to the cortical plate and differentiate either into astrocytes or neurons.  Somal translocation can occur at any time during development. 
Subsequent waves of neurons split the preplate by migrating along radial glial fibres to form the cortical plate. Each wave of migrating cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the surface.   It is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents. 
Tangential migration Edit
Most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. An example of tangential migration is the movement of interneurons from the ganglionic eminence to the cerebral cortex. One example of ongoing tangential migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb.
Axophilic migration Edit
Many neurons migrating along the anterior-posterior axis of the body use existing axon tracts to migrate along this is called axophilic migration. An example of this mode of migration is in GnRH-expressing neurons, which make a long journey from their birthplace in the nose, through the forebrain, and into the hypothalamus.  Many of the mechanisms of this migration have been worked out, starting with the extracellular guidance cues  that trigger intracellular signaling. These intracellular signals, such as calcium signaling, lead to actin  and microtubule  cytoskeletal dynamics, which produce cellular forces that interact with the extracellular environment through cell adhesion proteins  to cause the movement of these cells.
Multipolar migration Edit
There is also a method of neuronal migration called multipolar migration.   This is seen in multipolar cells, which in the human, are abundantly present in the cortical intermediate zone. They do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. 
The survival of neurons is regulated by survival factors, called trophic factors. The neurotrophic hypothesis was formulated by Victor Hamburger and Rita Levi Montalcini based on studies of the developing nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growing axons compete for limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophic support die by apoptosis. It is now clear that factors produced by a number of sources contribute to neuronal survival.
- (NGF): Rita Levi Montalcini and Stanley Cohen purified the first trophic factor, Nerve Growth Factor (NGF), for which they received the Nobel Prize. There are three NGF-related trophic factors: BDNF, NT3, and NT4, which regulate survival of various neuronal populations. The Trk proteins act as receptors for NGF and related factors. Trk is a receptor tyrosine kinase. Trk dimerization and phosphorylation leads to activation of various intracellular signaling pathways including the MAP kinase, Akt, and PKC pathways.
- CNTF: Ciliary neurotrophic factor is another protein that acts as a survival factor for motor neurons. CNTF acts via a receptor complex that includes CNTFRα, GP130, and LIFRβ. Activation of the receptor leads to phosphorylation and recruitment of the JAK kinase, which in turn phosphorylates LIFRβ. LIFRβ acts as a docking site for the STAT transcription factors. JAK kinase phosphorylates STAT proteins, which dissociate from the receptor and translocate to the nucleus to regulate gene expression.
- GDNF: Glial derived neurotrophic factor is a member of the TGFb family of proteins, and is a potent trophic factor for striatal neurons. The functional receptor is a heterodimer, composed of type 1 and type 2 receptors. Activation of the type 1 receptor leads to phosphorylation of Smad proteins, which translocate to the nucleus to activate gene expression.
Neuromuscular junction Edit
Much of our understanding of synapse formation comes from studies at the neuromuscular junction. The transmitter at this synapse is acetylcholine. The acetylcholine receptor (AchR) is present at the surface of muscle cells before synapse formation. The arrival of the nerve induces clustering of the receptors at the synapse. McMahan and Sanes showed that the synaptogenic signal is concentrated at the basal lamina. They also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as Agrin. Agrin induces clustering of AchRs on the muscle surface and synapse formation is disrupted in agrin knockout mice. Agrin transduces the signal via MuSK receptor to rapsyn. Fischbach and colleagues showed that receptor subunits are selectively transcribed from nuclei next to the synaptic site. This is mediated by neuregulins.
In the mature synapse each muscle fiber is innervated by one motor neuron. However, during development many of the fibers are innervated by multiple axons. Lichtman and colleagues have studied the process of synapses elimination.  This is an activity-dependent event. Partial blockage of the receptor leads to retraction of corresponding presynaptic terminals.
CNS synapses Edit
Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signals that mediate CNS synaptogenesis. Neurons in culture develop synapses that are similar to those that form in vivo, suggesting that synaptogenic signals can function properly in vitro. CNS synaptogenesis studies have focused mainly on glutamatergic synapses. Imaging experiments show that dendrites are highly dynamic during development and often initiate contact with axons. This is followed by recruitment of postsynaptic proteins to the site of contact. Stephen Smith and colleagues have shown that contact initiated by dendritic filopodia can develop into synapses.
Induction of synapse formation by glial factors: Barres and colleagues made the observation that factors in glial conditioned media induce synapse formation in retinal ganglion cell cultures. Synapse formation in the CNS is correlated with astrocyte differentiation suggesting that astrocytes might provide a synaptogenic factor. The identity of the astrocytic factors is not yet known.
Neuroligins and SynCAM as synaptogenic signals: Sudhof, Serafini, Scheiffele and colleagues have shown that neuroligins and SynCAM can act as factors that induce presynaptic differentiation. Neuroligins are concentrated at the postsynaptic site and act via neurexins concentrated in the presynaptic axons. SynCAM is a cell adhesion molecule that is present in both pre- and post-synaptic membranes.
Activity dependent mechanisms in the assembly of neural circuits Edit
The processes of neuronal migration, differentiation and axon guidance are generally believed to be activity-independent mechanisms and rely on hard-wired genetic programs in the neurons themselves. Research findings however have implicated a role for activity-dependent mechanisms in mediating some aspects of these processes such as the rate of neuronal migration,  aspects of neuronal differentiation  and axon pathfinding.  Activity-dependent mechanisms influence neural circuit development and are crucial for laying out early connectivity maps and the continued refinement of synapses which occurs during development.  There are two distinct types of neural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. Spontaneous activity occurs early during neural circuit development even when sensory input is absent and is observed in many systems such as the developing visual system,   auditory system,   motor system,  hippocampus,  cerebellum  and neocortex. 
Experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicators and optogenetic techniques have shed light on the nature and function of these early bursts of activity.   They have distinct spatial and temporal patterns during development  and their ablation during development has been known to result in deficits in network refinement in the visual system.  In the immature retina, waves of spontaneous action potentials arise from the retinal ganglion cells and sweep across the retinal surface in the first few postnatal weeks.  These waves are mediated by neurotransmitter acetylcholine in the initial phase and later on by glutamate.  They are thought to instruct the formation of two sensory maps- the retinotopic map and eye-specific segregation.  Retinotopic map refinement occurs in downstream visual targets in the brain-the superior colliculus (SC) and dorsal lateral geniculate nucleus (LGN).  Pharmacological disruption and mouse models lacking the β2 subunit of the nicotinic acetylcholine receptor has shown that the lack of spontaneous activity leads to marked defects in retinotopy and eye-specific segregation. 
In the developing auditory system, developing cochlea generate bursts of activity which spreads across the inner hair cells and spiral ganglion neurons which relay auditory information to the brain.  ATP release from supporting cells triggers action potentials in inner hair cells.  In the auditory system, spontaneous activity is thought to be involved in tonotopic map formation by segregating cochlear neuron axons tuned to high and low frequencies.  In the motor system, periodic bursts of spontaneous activity are driven by excitatory GABA and glutamate during the early stages and by acetylcholine and glutamate at later stages.  In the developing zebrafish spinal cord, early spontaneous activity is required for the formation of increasingly synchronous alternating bursts between ipsilateral and contralateral regions of the spinal cord and for the integration of new cells into the circuit.  In the cortex, early waves of activity have been observed in the cerebellum and cortical slices.  Once sensory stimulus becomes available, final fine-tuning of sensory-coding maps and circuit refinement begins to rely more and more on sensory-evoked activity as demonstrated by classic experiments about the effects of sensory deprivation during critical periods. 
Contemporary diffusion-weigthted MRI techniques may also uncover the macroscopic process of axonal development. The connectome can be constructed from diffusion MRI data: the vertices of the graph correspond to anatomically labelled gray matter areas, and two such vertices, say u and v, are connected by an edge if the tractography phase of the data processing finds an axonal fiber that connects the two areas, corresponding to u and v.
Numerous braingraphs, computed from the Human Connectome Project can be downloaded from the http://braingraph.org site. The Consensus Connectome Dynamics (CCD) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the Budapest Reference Connectome Server.   The Budapest Reference Connectome Server (http://connectome.pitgroup.org) depicts the cerebral connections of n=418 subjects with a frequency-parameter k: For any k=1,2. n one can view the graph of the edges that are present in at least k connectomes. If parameter k is decreased one-by-one from k=n through k=1 then more and more edges appear in the graph, since the inclusion condition is relaxed. The surprising observation is that the appearance of the edges is far from random: it resembles a growing, complex structure, like a tree or a shrub (visualized on the animation on the left).
It is hypothesized in  that the growing structure copies the axonal development of the human brain: the earliest developing connections (axonal fibers) are common at most of the subjects, and the subsequently developing connections have larger and larger variance, because their variances are accumulated in the process of axonal development.
Several motorneurons compete for each neuromuscular junction, but only one survives until adulthood.  Competition in vitro has been shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. In vivo, it is suggested that muscle fibres select the strongest neuron through a retrograde signal.
Individual Neurons Reveal Complexity Of Memory Within The Brain
An investigation of the activity of individual human nerve cells during the act of memory indicates that the brain&rsquos nerve cells are even more specialized than many people think &ndash no pun intended.
Although nerve cells that change activity during the use of memory are widely distributed in the brain, individual neurons generally respond to specific aspects of memory.
"For the first time, we&rsquove been able to show differences within regions of the temporal lobe in the way individual neurons respond to memory. Everything we&rsquove done to this point was to show that there are individual neurons that change activity --but we hadn&rsquot been able to sort them out in any meaningful way. Now we can," says Dr. George Ojemann, professor of neurological surgery at the University of Washington.
The findings appear in the January 2002 issue of Nature Neuroscience.
Ojemann is an internationally renowned neurosurgeon who has developed surgical techniques for treating epilepsy, brain tumors and Parkinsonism, and ways to explore the detailed organization of the human brain for language, memory, thought and learning. He has co-authored two books for lay readers on the higher functions of the brain: Inside the Brain and Conversations with Neil's Brain.
This research involves patients with epilepsy who were awake during surgery and agreed to respond to requests to recall words, names of pictures and sounds. The recordings were from relatively healthy brain tissue that must be removed in order to reach problematic parts of the brain responsible for epileptic seizures. In a typical procedure, surgeons insert four microelectrodes and record the electrical activity as neurons communicate with other cells. After the microelectrodes are in place, patients are asked questions that measure stages of memory.
The microelectrodes, sharpened tungsten wire about the thickness of a human hair, identify electric impulses from neurons. There are only a few programs worldwide that have investigated neuronal activity changes with human cognition. Given the size and complexity of neurons and their interconnections, it is difficult to measure the activity of any given neuron for a given time. The electrodes pick up discharges of a pool of neurons that are then separated into activity of individual neurons based on the shape of their individual discharges.
The latest study was able to identify the behavior of 105 neurons at 57 sites in 26 patients before, Ojemann says, his team&rsquos largest sample was about 25 neurons.
The findings reinforce the message that neurons are very specialized. For example, researchers identified 16 of the 105 neurons that significantly changed activity with different stages of memory &ndash encoding, storage and retrieval &ndash and found that in 13 of those, changes were observed in only one modality (auditory, six text, four objects, three).
"We just don&rsquot find neurons that are generic memory neurons. What we find are neurons that show statistically significant relationships to memory for a particular thing," Ojemann says.
There are three regional differences in brain activity that have not been noted before:
* There is a cluster of neurons that changes activity from encoding, to storage, to retrieval, in the basal temporal area, below the temporal lobe.
* Neurons that may help people recall something quickly after they have seen it earlier in the day &ndash what scientists call &lsquoimplicit memory&rsquo -- seem very active in the superior temporal gyrus of the temporal lobe.
* There are neurons in the language-dominant hemisphere that respond to more than one modality &ndash memory of both visual and auditory material.
At this point, the research is helping to illuminate the vast mysteries of the human brain. Someday, scientists may be able to use this knowledge to assist ailing brains. For example, it may be possible to externally activate neurons related to memory encoding in order to enhance memory.
TELEVISION PROGRAM: Dr. Ojemann&rsquos work will be featured on the Discovery Health cable channel during a documentary on brain surgery.The program airs 6 p.m. P.T., 9 p.m. E.T., on Sunday, Jan. 6.
These studies are supported by a grant from the National Institute of Neurological Disorders and Stroke, and are a collaborative project with Professor David Corina of the UW Department of Psychology.
Materials provided by University Of Washington. Note: Content may be edited for style and length.
How close are you to your goal? And what has been the greatest challenge?
We are hoping to gradually close in on our goal. There are many hurdles, but we are making good progress. The interesting thing is that many different disciplines are coming together in order to help solve the problem. Our group consists of biologists, neuroscientists, engineers, mathematicians and physicists. Together, we are working on further developing a technology that has really only been available for the past ten years, and which was originally developed by physicists who were studying titanium oxide particles. So, this was all very far removed from biology. It took a while before anyone could even contemplate using these kinds of methods in the field of biology, but we are now ready to do just that: to finally bridge that gap. One of the challenges we are facing is creating cohesion and cooperation within an interdisciplinary group of researchers. Every discipline has its own language and every member of the group has to learn how to understand and communicate with the others.
Neuroscience / Neurobiology
The Intellectual Basis: Neurobiology is concerned with uncovering the biological mechanisms by which nervous systems mediate behavior. Over the past half century, much of neurobiology has focused on the cells of the nervous system. The structure and physiology of nerve cells (neurons) and supporting glial cells has been elucidated in considerable detail as well as the functional contacts (synapses) made between neurons. How individual nerve and receptor cells generate, carry, and transmit electrical and chemical signals is now well under-stood, and many substances that are used by neurons to communicate information have been identified. More recently, molecular biological approaches are revealing the molecules involved in carrying out neural activities, and we are rapidly gaining glimpses of how these molecules function.
As we move into the 21st century, increasing attention is being given to integrative or systems neurobiology -- the study of aggregates of neurons and functional circuits. How do assemblies of neurons give rise to the behaviors we associate with higher brain functions, from perception and control of movement to learning and memory? Increasingly, studies on both invertebrate and vertebrate nervous systems are asking such questions. A particularly intriguing problem is how nervous systems develop and establish their complex circuitry.
The MBB Track in Neuroscience (formerly Neurobiology) is intended to provide students with the tools to study nervous systems biologically -- from molecules to behavior. This tracks is necessarily broad, requiring students to study chemistry, physics, and mathematics as well as cellular, molecular, and behavioral biology. Students electing one of these tracks will be well prepared for graduate programs in biology or neurobiology as well as for medical school.
The neuronal encoding of information in the brain
We describe the results of quantitative information theoretic analyses of neural encoding, particularly in the primate visual, olfactory, taste, hippocampal, and orbitofrontal cortex. Most of the information turns out to be encoded by the firing rates of the neurons, that is by the number of spikes in a short time window. This has been shown to be a robust code, for the firing rate representations of different neurons are close to independent for small populations of neurons. Moreover, the information can be read fast from such encoding, in as little as 20 ms. In quantitative information theoretic studies, only a little additional information is available in temporal encoding involving stimulus-dependent synchronization of different neurons, or the timing of spikes within the spike train of a single neuron. Feature binding appears to be solved by feature combination neurons rather than by temporal synchrony. The code is sparse distributed, with the spike firing rate distributions close to exponential or gamma. A feature of the code is that it can be read by neurons that take a synaptically weighted sum of their inputs. This dot product decoding is biologically plausible. Understanding the neural code is fundamental to understanding not only how the cortex represents, but also processes, information.
► Neuronal encoding in the primate visual, olfactory, taste and hippocampal cortex. ► Most of the information is encoded by the firing rates of the neurons. ► Little additional information is available in stimulus-dependent synchronization. ► The population information increases close to linearly with the number of neurons. ► The code is sparse distributed, with firing rate distributions exponential or gamma.
Scientists get closer look at living nerve synapses
The brain hosts an extraordinarily complex network of interconnected nerve cells that are constantly exchanging electrical and chemical signals at speeds difficult to comprehend. Now, scientists at Washington University School of Medicine in St. Louis report they have been able to achieve -- with a custom-built microscope -- the closest view yet of living nerve synapses.
Understanding the detailed workings of a synapse -- the junction between neurons that govern how these cells communicate with each other -- is vital for modeling brain networks and understanding how diseases as diverse as depression, Alzheimer's or schizophrenia may affect brain function, according to the researchers.
The study is published March 23 in the journal Neuron.
Studying active rat neurons, even those growing in a dish, is a challenge because they are so small. Further, they move, making it difficult to keep them in focus at high magnifications under a light microscope.
"Synapses are little nanoscale machines that transmit information," said senior author Vitaly A. Klyachko, PhD, an associate professor of cell biology and physiology at the School of Medicine. "They're very difficult to study because their scale is below what conventional light microscopes can resolve. So what is happening in the active zone of a synapse looks like a blur.
"To remedy this, our custom-built microscope has a very sensitive camera and is extremely stable at body temperatures, but most of the novelty comes from the analysis of the images," he added. "Our approach gives us the ability to resolve events in the synapse with high precision."
Until now, close-up views of the active zone have been provided by electron microscopes. While offering resolutions of mere tens of nanometers -- about 1,000 times thinner than a human hair and smaller -- electron microscopes can't view living cells. To withstand bombardment by electrons, samples must be fixed in an epoxy resin or flash frozen, cut into extremely thin slices and coated in a layer of metal atoms.
"Most of what we know about the active zone is from indirect studies, including beautiful electron microscopy images," said Klyachko, also an associate professor of biomedical engineering at the School of Engineering & Applied Science. "But these are static pictures. We wanted to develop a way to see the synapse function."
A synapse consists of a tiny gap between two nerves, with one nerve serving as the transmitter and the other as the receiver. When sending signals, the transmitting side of the synapse releases little packages of neurotransmitters, which traverse the gap and bind to receptors on the receiving side, completing the information relay. On the transmitting side of the synapse the neurotransmitters at the active zone are packaged into synaptic vesicles.
"One of the most fundamental questions is: Are there many places at the active zone where a vesicle can release its neurotransmitters into the gap, or is there only one?" Klyachko said. "A lot of indirect measurements suggested there might be only one, or maybe two to three, at most."
In other words, if the active zone could be compared to a shower head, the question would be whether it functions more as a single jet or as a rain shower.
Klyachko and first author Dario Maschi, PhD, a postdoctoral researcher, showed that the active zone is more of a rain shower. But it's not a random shower there are about 10 locations dotted across the active zone that are reused too often to be left to chance. They also found there is a limit to how quickly these sites can be reused -- about 100 milliseconds must pass before an individual site can be used again. And at higher rates of vesicle release, the site usage tends to move from the center to the periphery of the active zone.
"Neurons often fire at 50 to 100 times per second, so it makes sense to have multiple sites," Klyachko said. "If one site has just been used, the active zone can still be transmitting signals through its other sites.
"We're studying the most basic machinery of the brain," he added. "Our data suggest these machines are extremely fine-tuned -- even subtle modulations may lead to disease. But before we can study disease, we need to understand how healthy synapses work."
Do individual neurons communicate with the origin of thoughts? - Biology
It's been known since the 16th century that neurons and blood vessels often traverse the body side by side but it was only more recently discovered that the growth of neuronal and vascular networks is controlled by the same molecules.
“Most interesting is the interaction between neurons and blood vessels in the cerebral cortex. To date, we know very little about how neurons communicate with endothelial cells in order to structure a functional network in the brain.” explains Prof. Dr. Amparo Acker-Palmer, who plans to assess these processes in the layering of the cerebral cortex during embryonic development.
During that time, neuronal cells migrate in an inside out manner, while blood vessels grow in the opposite direction, from the pial surface towards the ventricular surface. Since these two growth processes are coordinated, Acker-Palmer suspects that they are controlled by the same signaling molecules.
The microscope image of a mouse brain illustrates the close interaction between neurons (green), astrocytes (blue), and blood vessels (red) in the brain. The various cell populations appear in a specific pattern and interact with the neighboring cells. Credit: Goethe-Universität Frankfurt am Main
How dysfunction in the crosstalk may lead to cognitive impairments is one of the focuses of her research.
As model organisms her team uses genetically altered mice and zebrafish. Translucent zebrafish are the best suitable vertebrate model to visualize in vivo the dynamic events of cell-to-cell communication at the neurovascular interface. High-resolution electron microscopes will also be used to study these close connections between endothelial cells in the blood capillaries and glial cells at the blood-brain barrier.
Glial cells wrap around the blood capillaries and prevent harmful substances from the blood stream from entering the brain.
Acker-Palmer and her team aim at deciphering the molecular signaling pathways regulating the neurovascular interface. “If we can intervene in the mechanism and temporarily open the blood-brain barrier, we can insert active agents and find new approaches for treating dementia and mental illness,” says the neurobiologist.
In vivo-Imaging of the blood circulation system in a three-day-old zebrafish larva. The left picture shows a side view of the head, the middle picture a side view of the trunk and the right picture a back view of the head. Fluorescent reporter genes reveal that the blood vessels (green) are fully formed at this point. The individual blood cells (red) can also be seen circulating in the blood vessels.
Alexa Erdogan is currently pursuing a Master's in Space Systems Engineering at John Hopkins University. Although she originally started in molecular and cellular biology and neuroscience, she has since combined those fields with space science, leading to the pursuit of her ultimate final frontier: space neuroscience. Her prior research has delved into the role of microglia in ischemic preconditioning, while her current pursuits explore the impact that outer space has on neurological systems across various species. Outside of research, she tries to share her passion for science with other curious minds using science communication across various media, from print to podcast.