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ScienceWeek
NEUROSCIENCE: ON MICROCIRCUIT INHIBITION FLOW
The following points are made by W. Mittmann et al (Current Biology 2004 14:R837):
1) Inhibition in cortical circuits is mediated by interneurons using the neurotransmitter gamma-aminobutyric acid (GABA). These interneurons exhibit far more morphological diversity than excitatory neurons [1,2]. Anatomical studies have revealed that interneurons target distinct subcellular domains on principal neurons, such that specific populations of interneurons selectively target the axon, perisomatic region, and distal dendrites. These interneurons thus form intricate microcircuits, counteracting different sets of excitatory synapses. Such microcircuits may therefore define postsynaptic computational domains, where processing is regulated by the temporal and spatial activation of excitatory and inhibitory synapses as well as the integrative properties of the postsynaptic neurons.
2) It is not well understood how different inhibitory circuits are engaged by different patterns of activity in the brain. Functionally, activity-dependent inhibition has been divided into two different types: feedforward inhibition and feedback inhibition. Feedforward inhibition is provided by excitatory inputs that activate both pyramidal cells and inhibitory interneurons [3,4]. This disynaptic inhibition arrives at the postsynaptic neuron with a brief delay, and thus feedforward inhibition shortens the duration of excitatory postsynaptic potentials (EPSPs), limiting the time window for summation of EPSPs. Furthermore, spikes triggered by these EPSPs can only occur in the narrow time window of the shortened excitation, thus increasing the temporal precision of pyramidal cell output in response to excitatory input. In contrast, feedback inhibition is triggered by recurrent collaterals of the pyramidal cells, which therefore activate interneurons only when an output spike is generated [5]. Feedforward and feedback inhibition thus provide complementary controls of excitability: feedforward inhibition is regulated by the level of excitatory input, while feedback inhibition is proportional to the rate of output.
3) How do these different types of functional inhibition map onto the different anatomical classes of interneurons? Feedforward inhibition has been shown to activate interneurons that primarily target the perisomatic regions [4]. Recent work demonstrates that in the hippocampal CA1 region, feedback inhibition engages two distinct subtypes of interneuron, depending on the pattern of activity. Researchers have tracked the spatiotemporal distribution of recurrent inhibition by making simultaneous somatic and dendritic recordings from pyramidal neurons, while activating feedback inhibition by stimulating the axons of other pyramidal neurons in the alveus. With a single stimulus, recurrent inhibition was more prominent at the soma than at the dendrite; during a train of stimuli, however, the inhibition shifted from the soma into the dendritic tree. This shift of inhibition is apparently due to sequential activation of inhibitory synaptic conductances onto the soma and dendrite of the pyramidal neurons.
References (abridged):
1. Freund, T.F. and Buzsaki, G. (1996). Interneurons of the hippocampus. Hippocampus 6, 347-470
2. Somogyi, P., Tamas, G., Lujan, R. and Buhl, E.H. (1998). Salient features of synaptic organisation in the cerebral cortex. Brain Res. Brain Res. Rev. 26, 113-135
3. Buzsaki, G. (1984). Feed-forward inhibition in the hippocampal formation. Prog. Neurobiol. 22, 131-153
4. Pouille, F. and Scanziani, M. (2001). Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science 293, 1159-1163
5. Andersen, P., Eccles, J.C. and Loyning, Y. (1963). Recurrent inhibition in the hippocampus with identification of the inhibitory cell and its synapses. Nature 198, 540-542
Current Biology http://www.current-biology.com
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MICROCIRCUITRY IN THE CEREBRAL CORTEX
Notes by ScienceWeek:
The cerebral cortex is a thin surface layering of nerve cells of the brain, the region only several millimeters thick but covering all of the brain surface. This is the part of the central nervous system most intimately involved with the so-called "higher faculties", although the cortex operates in concert with other parts of the brain. The structure is primitive in lower mammals, and is found progressively more pronounced and with greater surface area in primates and man.
The following points are made by J. Kozloski et al (Science 2001 293:868):
1) The cortical microcircuit, i.e., the intra- and interlaminar connections within a local neocortical region, is still largely unknown, although its characterization is essential to any theory of cortical function. The search for rules governing the cortical microcircuit has revealed wide diversities of neurons, columnar and horizontal connectivity, and distinct interlaminar and long-range projections (output connections). Connections from other cortical neurons can be precise, targeting specific postsynaptic locations.
2) However, connectivity rules among excitatory cells, which constitute the vast majority of cortical neurons, remain unclear. Some studies indicate that excitatory neurons are weakly interconnected in probabilistic patterns, so that specificity can be found only at the statistical level. At the same time, because the number of different classes of neocortical neurons is still unknown and could approach several hundreds, any apparent lack of target specificity might result from heterogeneous sampling. Also, physiological studies indicate remarkable circuit specificity.
3) The authors used an optical probing technique to detect postsynaptic targets of neurons in brain slices, and then chose targets for dual recordings. By imaging hundreds of neurons simultaneously, while electrically stimulating a trigger cell, the authors optically detected the "follower" neurons connected to it. The authors suggest their data reveal precisely organized microcircuits.
Science http://www.sciencemag.org
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NEUROBIOLOGY: ON THE DEVELOPMENT OF HARD-WIRED CIRCUITS
The following points are made by Lisa Stowers (Current Biology 2004 14:R62):
1) During sensory development, abundant neurons are created in the brain that become functional by precisely extending processes to synapse with determined targets. In contrast to the visual or somatosensory system, olfactory information is mediated by a large number of distinct receptor neurons, randomly intermingled in the olfactory epithelium, and the axons from cells expressing identical ligand receptors precisely converge on a defined second order neuron. This poses a number of molecular challenges to ensure that a stereotyped, hard-wired circuit properly develops so as to mediate perception. Work on development of the olfactory system in Drosophila is beginning to elucidate the principles that underlie this process.
2) Neuronal circuit formation has been well characterized in the visual system, where positional sensory information from neighboring neurons must be preserved at each synapse so as faithfully to represent the environment [1,2]. Gradients of ephrins and their receptors govern the position of synapse formation of individual neurons, which is then refined by coordinated neuronal activity [3]. This, however, does not appear to be the only strategy for specifying neuronal targets, as demonstrated in the mammalian olfactory system where activity is dispensable [4,5] and the only identified essential molecular components of this process are the olfactory receptor genes themselves. One might assume that the olfactory receptors detect ligand cues which are important for correct wiring of the system, but at present no cues of this kind have been discovered.
3) Convergence of the sensory neurons is only half of this complex process. The dendrites of the second order neurons --mitral cells in vertebrates or projection neurons in invertebrates -- are also targeted to this defined region to form glomeruli. Several studies on vertebrates and invertebrates have suggested that the wiring pattern at this level of the olfactory system is instructed by the incoming receptor neurons. Specifically, genetic ablation of the mitral cells in the mouse was found not to disrupt the convergence and stereotyped position of incoming receptor neurons. In the moth, removal of the antennae, and thus the receptor neurons, prevented normal glomerular formation, while surgical dissection of projection neurons did not disrupt receptor neuron convergence. And in Drosophila mutants where there is a failure to establish a proposed pioneer class of receptor neurons, the development of glomeruli is disrupted. Together, these studies suggest that specific wiring at the first relay in the olfactory system is precisely patterned by receptor neurons which instruct the second order neurons to organize appropriately.
References (abridged):
1. Simon, D.K. and O'Leary, D.D. (1992). Development of topographic order in the mammalian retinocollicular projection. J. Neurosci. 12, 1212-1232
2. Katz, L.C. and Shatz, C.J. (1996). Synaptic activity and the construction of cortical circuits. Science 274, 1133-1138
3. Yates, P.A., Roskies, A.L., McLaughlin, T., and O'Leary, D.D. (2001). Topographic-specific axon branching controlled by ephrin-As is the critical event in retinotectal map development. J. Neurosci. 21, 8548-8563
4. Lin, D.M., Wang, F., Lowe, G., Gold, G.H., Axel, R., Ngai, J., and Brunet, L. (2000). Formation of precise connections in the olfactory bulb occurs in the absence of odorant-evoked neuronal activity. Neuron 26, 69-80
5. Zheng, C., Feinstein, P., Bozza, T., Rodriguez, I., and Mombaerts, P. (2000). Peripheral olfactory projections are differentially affected in mice deficient in a cyclic nucleotide-gated channel subunit. Neuron 26, 81-91
Current Biology http://www.current-biology.com
ScienceWeek http://scienceweek.com
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