Vision is critical for the functional and structural maturation of connections in the mammalian visual system. Visual experience, however, is a subset of a more general requirement for neural activity in transforming immature circuits into the organized connections that subserve adult brain function. Early in development, internally generated spontaneous activity sculpts circuits on the basis of the brain's "best guess" at the initial configuration of connections necessary for function and survival. With maturation of the sense organs, the developing brain relies less on spontaneous activity and increasingly on sensory experience. The sequential combination of spontaneously generated and experience-dependent neural activity endows the brain with an ongoing ability to accommodate to dynamically changing inputs during development and throughout life.

Synaptic Activity and the Construction of Cortical Circuits

Src family protein tyrosine kinases are activated following engagement of many different classes of cellular receptors and participate in signaling pathways that control a diverse spectrum of receptor-induced biological activities. While several of these kinases have evolved to play distinct roles in specific receptor pathways, there is considerable redundancy in the functions of these kinases, both with respect to the receptor pathways that activate these kinases and the downstream effectors that mediate their biological activities. This chapter reviews the evidence implicating Src family kinases in specific receptor pathways and describes the mechanisms leading to their activation, the targets that interact with these kinases, and the biological events that they regulate.

Cellular functions regulated by src family kinases

Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.

/pdf/homeostatic-plasticity-in-the-developing-nervous-system-vvjoqmmjmb.pdf

Homeostatic plasticity in the developing nervous system

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

It has been clear for almost two decades that cortical representations in adult animals are not fixed entities, but rather, are dynamic and are continuously modified by experience. The cortex can preferentially allocate area to represent the particular peripheral input sources that are proportionally most used. Alterations in cortical representations appear to underlie learning tasks dependent on the use of the behaviorally important peripheral inputs that they represent. The rules governing this cortical representational plasticity following manipulations of inputs, including learning, are increasingly well understood. In parallel with developments in the field of cortical map plasticity, studies of synaptic plasticity have characterized specific elementary forms of plasticity, including associative long-term potentiation and long-term depression of excitatory postsynaptic potentials. Investigators have made many important strides toward understanding the molecular underpinnings of these fundamental plasticity processes and toward defining the learning rules that govern their induction. The fields of cortical synaptic plasticity and cortical map plasticity have been implicitly linked by the hypothesis that synaptic plasticity underlies cortical map reorganization. Recent experimental and theoretical work has provided increasingly stronger support for this hypothesis. The goal of the current paper is to review the fields of both synaptic and cortical map plasticity with an emphasis on the work that attempts to unite both fields. A second objective is to highlight the gaps in our understanding of synaptic and cellular mechanisms underlying cortical representational plasticity.

/pdf/cortical-plasticity-from-synapses-to-maps-2j9eoi9428.pdf

CORTICAL PLASTICITY: From Synapses to Maps

Mutant mice and neuroscience: Recommendations concerning genetic background

1. Extracellular spike recordings were made from single cells in various layers of barrel cortex in adult rats anesthetized with urethan. Response magnitude and latency differences to brief 1.14 degrees deflections of mystacial vibrissae of center (principal) and surround receptive-field vibrissae were measured. Latency differences for pairs of cells in the same penetration to stimulation of the principal vibrissa were also collected. In separate experiments the domains of layer IV cells were mapped for their influence by a single vibrissa and their latencies to this vibrissa were recorded. In all experiments precise locations of layer IV cells in each penetration were identified using dye-lesioning and cytochrome oxidase staining of tangential sections. 2. The results suggest that principal vibrissa data are relayed radially in a column of neurons before parallel relay to adjacent columns. To the principal vibrissa, layers IV and Vb neurons discharged earliest, with layers II and III on average 2 and 3 ms later, respectively. Serial relay from layers IV to III to II was suggested to be the most common event. Although layer Va cells fired next, a single-column organization is not suggested for them because differences in latency or response magnitude to their principal and immediate surround vibrissae were not significant. Layer II, III and IV cells showed no statistical difference in latency to the nearest surround vibrissa but fired significantly later than to their principal input. 3. Because, from our previous studies, surround receptive fields of barrel cells in rat S1 cortex appear to be constructed intracortically, these data suggest a parallel column-column relay for their construction. Horizontal relay between barrels occurred first within the septae between barrels. Mean intracortical transmission velocities were calculated at approximately 0.05 m/s for column-column information transfer.

Flow of excitation within rat barrel cortex on striking a single vibrissa.

Recordings were made from neurons in layers II, III, and IV of rat barrel cortex. The animals were raised either from the day of birth (P0) or from P2, P4, or P7 with just the D1 vibrissa protruding on one side of the face and the contralateral side intact. Follicles were not ablated, but vibrissae were carefully removed by applying steady tension to the base of each vibrissa. Deprivation was continued until the day of recording (P30-P90), though in most cases vibrissae were allowed to regrow for 4–7 d prior to recording. The area of cortex driven by stimulating the spared D1 vibrissa was found to be enlarged in uni-vibrissae animals, but the characteristic anatomical map of the barrel field, defined by cytochrome oxidase staining, retained its normal form. In animals deprived from P0, layer IV cells outside the D1 barrel responded with short latencies (5–10 msec) to D1 stimulation, a condition never observed in normally reared animals. Short-latency responses to stimulation of regrown, deprived vibrissae were still present in layer IV despite the deprivation. Plasticity decreased rapidly in layer IV between P0 and P4 as judged by two measures: first, the percentage of cells in neighboring barrels that showed short- latency responses to D1 fell from 30% in P0 deprived animals to 18% in P2 and 13% in P4 deprived animals. Second, the percentage of cells in barrels surrounding D1 with larger responses to D1 stimulation than to stimulation of their anatomically related vibrissa also fell from 37% in P0 to 23% in P2 and 12% in P4 deprived animals. The percentage of “shifted cells” showed no further reduction in P7 deprived animals (14%). Plasticity in layers II and III showed little sign of decreasing between P2 and P7 after an initial drop between P0 and P2. Therefore, deprivation started at P4 and P7 had a far greater effect on layers II and III than on layer IV. In animals deprived from P4 onward, not only were responses to D1 stimulation greater in barrels neighboring D1 (in layers II/III), but responses were smaller to principal vibrissa stimulation. This suggests increased lateral transmission from the “experienced” barrel and a failure of vertical transmission within the “deprived” barrels. These results show that changes in the balance of experience acquired through vibrissae can affect development of connectivity in the barrel cortex. The main locus of plasticity is cortical when deprivations are started at P4 and beyond.(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.jneurosci.org/content/jneuro/12/5/1826.full.pdf

A critical period for experience-dependent synaptic plasticity in rat barrel cortex

The size and response magnitude of receptive fields were evaluated for cells in the rat cortical barrel-field by using standard vibrissal deflections of 1.14 degrees. Such stimuli fell within the plateau region of stimulus-response curves. The response of all neurones to all vibrissae within and surrounding centre-receptive fields were analysed for probability and latency of response. It was found that cells in supragranular layers had small centre-receptive fields (average 1.6 vibrissae) with small excitatory surrounds (1.5 vibrissae) while cells in the granular layers had small, powerful centre-receptive fields (1.4) with moderately large excitatory surrounds (2.6). Neurones in infragranular layers possessed large but weak centre-receptive fields (2.6) with large surrounds (3.5). Sixty-four neurones in layer IV were studied, the precise locations of which were identified by using dye lesioning and cytochrome oxidase staining. There were no differences in receptive field size for cells within septa and barrel hollows, but the latter were twice as likely to produce two or more spikes per stimulus from the principal vibrissa (65% against 33%). Histological analysis showed that the principal vibrissa was synonymous with the appropriate vibrissa for the barrel on 86% (55 of 64) of occasions. A quantitative analysis of convergent input to three neighbouring barrels (E1, E2, and D1) showed considerable graded overlap of receptive field surrounds, although facial hair adjacent to the mystacial pad only influenced cells on the edge of the barrel-field. Individual vibrissae exhibited significant divergent input to adjacent inappropriate barrels, being preferentially directed to distant septal rather than barrel hollow cells. An analysis of latencies showed that 40% of barrel hollow cells and 48% of barrel septal cells responded at short (less than 10 ms) latencies to their appropriate vibrissa. In contrast, responses to inappropriate vibrissae were overwhelmingly of long latency (10-greater than 30 ms), only 2% of inappropriate responses from barrel hollow cells and 13% from septal cells being of short latency. These results suggest that direct inputs largely project to appropriate barrels. The possibility that divergent inputs are generated by intracortical mechanisms is discussed.

Kevin Fox

Papers

Mutant mice and neuroscience: Recommendations concerning genetic background

Flow of excitation within rat barrel cortex on striking a single vibrissa.

A critical period for experience-dependent synaptic plasticity in rat barrel cortex

Spatiotemporal convergence and divergence in the rat S1 "barrel" cortex.

Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex.