Thalamocortical Afferents Research Articles

Functional Subregions in Primary Auditory Cortex Defined by Thalamocortical Terminal Arbors: An Electrophysiological and Anterograde Labeling Study

Several functional maps have been described in primary auditory cortex, including those related to frequency, tuning, latency, binaurality, and intensity. Many of these maps are arranged in a discontinuous or patchy manner. Similarly, thalamocortical projections arising from the ventral division of the medial geniculate body to the primary auditory cortex are also patchy. We used anterograde labeling and electrophysiological methods to examine the relationship between thalamocortical patches and auditory cortical maps. Biotinylated dextran-amine was deposited into physiologically characterized sites in the ventral division of the medial geniculate body of New Zealand white rabbits. Approximately 7 d later, the animal was again anesthetized and the ipsilateral auditory cortex was mapped with tungsten microelectrodes. Multi-unit physiological data were obtained for the following characteristics: best frequency (BF), binaurality, response type, latency, sharpness of tuning, and threshold. Immunocytochemical methods were used to reveal the injection site in the ventral division of the medial geniculate body as well as the anterogradely labeled thalamocortical afferents in the auditory cortex. In 86% of the cases (12 of 14), entry into a thalamocortical patch was associated with a marked change in physiological responses. A consistent BF and binaural class were usually observed within a patch. The patches appear to innervate distinct functional regions coding frequency and binaurality. A model is presented showing how patchy thalamocortical projections participate in the formation of tonotopic and binaural maps in primary auditory cortex.

Thalamocortical control of feed-forward inhibition in awake somatosensory 'barrel' cortex.

Intracortical inhibition plays a role in shaping sensory cortical receptive fields and is mediated by both feed-forward and feedback mechanisms. Feed-forward inhibition is the faster of the two processes, being generated by inhibitory interneurons driven by monosynaptic thalamocortical (TC) input. In principle, feed-forward inhibition can prevent targeted cortical neurons from ever reaching threshold when TC input is weak. To do so, however, inhibitory interneurons must respond to TC input at low thresholds and generate spikes very quickly. A powerful feed-forward inhibition would sharpen the tuning characteristics of targeted cortical neurons, and interneurons with sensitive and broadly tuned receptive fields could mediate this process. Suspected inhibitory interneurons (SINs) with precisely these properties are found in layer 4 of the somatosensory (S1) 'barrel' cortex of rodents and rabbits. These interneurons lack the directional selectivity seen in most cortical spiny neurons and in ventrobasal TC afferents, but are much more sensitive than cortical spiny neurons to low-amplitude whisker displacements. This paper is concerned with the activation of S1 SINs by TC impulses, and with the consequences of this activation. Multiple TC neurons and multiple S1 SINs were simultaneously studied in awake rabbits, and cross-correlation methods were used to examine functional connectivity. The results demonstrate a potent, temporally precise, dynamic and highly convergent/divergent functional input from ventrobasal TC neurons to SINs of the topographically aligned S1 barrel. Whereas the extensive pooling of convergent TC inputs onto SINs generates sensitive and broadly tuned inhibitory receptive fields, the potent TC divergence onto many SINs generates sharply synchronous activity among these elements. This TC feed-forward inhibitory network is well suited to provide a fast, potent, sensitive and broadly tuned inhibition of targeted spiny neurons that will suppress spike generation following all but the most optimal feed-forward excitatory inputs.

Thalamocortical Bursts Trigger Recurrent Activity in Neocortical Networks: Layer 4 as a Frequency-Dependent Gate

Sensory information reaches the cortex via thalamocortical (TC) synapses in layer 4. Thalamic relay neurons that mediate information flow to cortex operate in two distinct modes, tonic and burst firing. Burst firing has been implicated in enhancing reliability of information flow between individual neurons. However, little is known about how local networks of neocortical neurons respond to different temporal patterns of TC activity. We studied cortical activity patterns evoked by stimulating TC afferents at different frequencies, using a combination of electrophysiology and calcium imaging in TC slices that allowed for the reconstruction of spatiotemporal activity with single-cell resolution. Stimulation of TC axons at low frequencies triggered action potentials in only a small number of layer 4 neurons. In contrast, brief high-frequency stimulus trains triggered widespread recurrent activity in populations of neurons in layer 4 and then spread into adjacent layers 2/3 and 5. Recurrent activity had a clear threshold, typically lasted 300 msec, and could be evoked repetitively at frequencies up to 0.5 Hz. Moreover, the spatial extent of recurrent activity was controlled by the TC pattern of activity. Recurrent activity triggered within the highly interconnected networks of layer 4 might act to selectively amplify and redistribute transient high-frequency TC inputs, filter out low-frequency inputs, and temporarily preserve a record of past sensory activity.

Effects of elevated serotonin levels on patterns of GAP-43 expression during barrel development in rat somatosensory cortex

Elevating cortical serotonin (5-HT) in rats with clorgyline, a monoamine oxidase A (MAO A) inhibitor, from postnatal day (P-0) to P-6 delays the organization of thalamocortical afferent fibers into a vibrissae-related pattern in the somatosensory cortex (S-I). Despite continued elevation of cortical 5-HT through P-8, the thalamocortical fibers do form, albeit with some delay, a characteristic vibrissae pattern of barrels in layer IV of S-I by P-8. The growth-associated protein, GAP-43, is transiently expressed in developing S-I cortex of normal rats in a vibrissae related pattern until P-7. After P-7, GAP-43 expression is reduced in the barrel centers and increased in the septa. The present study evaluated the effect of elevated 5-HT levels on the distribution of GAP-43 immunoreactivity in S-I. We employed 5-HT immunocytochemistry and 1,1′-dioctadecyl-3,3,3″,3′-tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic radiations to confirm a ‘barrelless’ phenotype in P-6 clorgyline-treated animals and a recovered barrel pattern in treated animals allowed to survive until P-8 and P-10. GAP-43 immunocytochemistry was used to evaluate the cortical distribution of this protein in similarly treated littermates. Continuous inhibition of MAO A from P-0 to P-6 resulted in a corresponding loss of the GAP-43 vibrissae-related pattern at P-6. Despite continued elevation of cortical 5-HT until P-8 and P-10, the characteristic vibrissae-complementary pattern of GAP-43 emerged with expression concentrated in the septa and rows. GAP-43 vibrissae-related thalamocortical axon pattern never appeared in the clorgyline-treated animals. Thus, while elevated 5-HT delays development of a vibrissae-related pattern of thalamocortical afferents, it does not appear to alter the time when a GAP-43 vibrissae-related complementary pattern emerges.

Functional synaptic projections onto subplate neurons in neonatal rat somatosensory cortex.

Subplate neurons (SPn) play an important role in the formation of thalamocortical connections during early development and show glutamatergic and GABAergic spontaneous synaptic activity. We characterized these synaptic inputs by performing whole-cell recordings from SPn in somatosensory cortical slices of postnatal day 0-3 rats. At -70 mV, electrical stimulation of the thalamocortical afferents elicited in 68% of the SPn a monosynaptic CNQX-sensitive postsynaptic current (PSC). These fast PSCs were mediated by AMPA receptors, because they were prolonged by cyclothiazide and blocked by GYKI 52466. On membrane depolarization, thalamocortical stimulation elicited in 50% of the cells an additional slow monosynaptic component mediated by NMDA receptors. Stimulation of the cortical plate evoked in 72% of SPn a monosynaptic AMPA receptor-mediated PSC with an additional NMDA component at depolarized membrane potentials and in 40% of the investigated cells polysynaptic responses, depending on GABA(A) and NMDA receptors. Stimulation of the subplate elicited in 67% of SPn a monosynaptic dual-component PSC mediated by AMPA and NMDA receptors activated at -70 mV and in 12% of SPn a monosynaptic single-component PSC mediated by AMPA receptors with an additional NMDA component activated at depolarized membrane potentials. A monosynaptic GABAergic response could be observed in 68% of SPn after stimulation of the subplate. In gramicidin-perforated patch recordings, bath application of GABA caused membrane depolarization to -40 mV and elicited action potentials. These results demonstrate that SPn receive distinct functional synaptic inputs arising from the thalamus, cortical plate, and subplate, indicating that SPn are capable of integrating and processing information from cortical and subcortical regions.

Functional Synaptic Projections onto Subplate Neurons in Neonatal Rat Somatosensory Cortex

Subplate neurons (SPn) play an important role in the formation of thalamocortical connections during early development and show glutamatergic and GABAergic spontaneous synaptic activity. We characterized these synaptic inputs by performing whole-cell recordings from SPn in somatosensory cortical slices of postnatal day 0–3 rats. At –70 mV, electrical stimulation of the thalamocortical afferents elicited in 68% of the SPn a monosynaptic CNQX-sensitive postsynaptic current (PSC). These fast PSCs were mediated by AMPA receptors, because they were prolonged by cyclothiazide and blocked by GYKI 52466. On membrane depolarization, thalamocortical stimulation elicited in 50% of the cells an additional slow monosynaptic component mediated by NMDA receptors. Stimulation of the cortical plate evoked in 72% of SPn a monosynaptic AMPA receptor-mediated PSC with an additional NMDA component at depolarized membrane potentials and in 40% of the investigated cells polysynaptic responses, depending on GABA_A and NMDA receptors. Stimulation of the subplate elicited in 67% of SPn a monosynaptic dual-component PSC mediated by AMPA and NMDA receptors activated at –70 mV and in 12% of SPn a monosynaptic single-component PSC mediated by AMPA receptors with an additional NMDA component activated at depolarized membrane potentials. A monosynaptic GABAergic response could be observed in 68% of SPn after stimulation of the subplate. In gramicidin-perforated patch recordings, bath application of GABA caused membrane depolarization to –40 mV and elicited action potentials. These results demonstrate that SPn receive distinct functional synaptic inputs arising from the thalamus, cortical plate, and subplate, indicating that SPn are capable of integrating and processing information from cortical and subcortical regions.

Cortical activation patterns evoked by afferent axons stimuli at different frequencies: an in vitro voltage-sensitive dye imaging study

Voltage-sensitive dye imaging (VDI) of cortical activation patterns generated by electrical stimulation of thalamocortical afferents axons at different frequencies was studied, in vitro, using mouse brain slices. The study demonstrated that thalamocortical afferent axons stimulation could follow frequencies as high as 120 Hz without marked reduction. By contrast the power spectral density amplitude ratio in cortical layer 4 demonstrated a rapidly sigmoidal reduction at frequencies above 60 Hz. Similar findings were obtained with direct cortical afferent axons stimulation that obviated possible interactions at thalamic level. As pre-synaptic afferent field potentials, simultaneously recorded with the VDI at cortical level, followed higher stimulation frequency, it is concluded that cortical activity reduction is secondary to synaptic transmission failure. This interpretation agrees with the result from deep-brain stimulation (DBS) in humans in which high-frequency stimulation produces comparable therapeutic results, as does stereotaxic brain lesioning.

Maturation of human auditory cortex: implications for speech perception.

This project traced the maturation of the human auditory cortex from midgestation to young adulthood, using immunostaining of axonal neurofilaments to determine the time of onset of rapid conduction. The study identified 3 developmental periods, each characterized by maturation of a different axonal system. During the perinatal period (3rd trimester to 4th postnatal month), neurofilament expression occurs only in axons of the marginal layer. These axons drive the structural and functional development of cells in the deeper cortical layers, but do not relay external stimuli. In early childhood (6 months to 5 years), maturing thalamocortical afferents to the deeper cortical layers are the first source of input to the auditory cortex from lower levels of the auditory system. During later childhood (5 to 12 years), maturation of commissural and association axons in the superficial cortical layers allows communication between different subdivisions of the auditory cortex, thus forming a basis for more complex cortical processing of auditory stimuli.

Rapid Ocular Dominance Plasticity Requires Cortical but Not Geniculate Protein Synthesis

Synaptic plasticity is a multistep process in which rapid, early phases eventually give way to slower, more enduring stages. Diverse forms of synaptic change share a common requirement for protein synthesis in the late stages of plasticity, which are often associated with structural rearrangements. Ocular dominance plasticity in the primary visual cortex (V1) is a long-lasting form of activity-dependent plasticity comprised of well-defined physiological and anatomical stages. The molecular events underlying these stages remain poorly understood. Using the protein synthesis inhibitor cycloheximide, we investigated a role for protein synthesis in ocular dominance plasticity. Suppression of cortical, but not geniculate, protein synthesis impaired rapid ocular dominance plasticity, while leaving neuronal responsiveness intact. These findings suggest that structural changes underlying ocular dominance plasticity occur rapidly following monocular occlusion, and cortical changes guide subsequent alterations in thalamocortical afferents.

Cortical activation patterns evoked by afferent axons stimuli at different frequencies: an in vitro voltage-sensitive dye imaging study

Voltage-sensitive dye imaging (VDI) of cortical activation patterns generated by electrical stimulation of thalamocortical afferents axons at different frequencies was studied, in vitro, using mouse brain slices. The study demonstrated that thalamocortical afferent axons stimulation could follow frequencies as high as 120 Hz without marked reduction. By contrast the power spectral density amplitude ratio in cortical layer 4 demonstrated a rapidly sigmoidal reduction at frequencies above 60 Hz. Similar findings were obtained with direct cortical afferent axons stimulation that obviated possible interactions at thalamic level. As pre-synaptic afferent field potentials, simultaneously recorded with the VDI at cortical level, followed higher stimulation frequency, it is concluded that cortical activity reduction is secondary to synaptic transmission failure. This interpretation agrees with the result from deep-brain stimulation (DBS) in humans in which high-frequency stimulation produces comparable therapeutic results, as does stereotaxic brain lesioning.

Developmental onset of functional activity in the wallaby whisker cortex in response to stimulation of the infraorbital nerve

This study used the extrauterine development of a marsupial wallaby to investigate the onset of functional activity in the somatosensory pathway from the whiskers. In vivo recordings were made from the somatosensory cortex from postnatal day (P) 55 to P138, in response to electrical stimulation of the infraorbital nerve supplying the mystacial whiskers. Current source density analysis was used to localize the responses within the cortical depth. This was correlated with development of cortical lamination and the onset of whisker-related patches, as revealed by cytochrome oxidase. The earliest evoked activity occurred at P61, when layers 5 and 6 are present, but layer 4 has not yet developed. This activity showed no polarity reversal with depth, suggesting activity in thalamocortical afferents. By P72 synaptic responses were detected in developing layer 4 and cytochrome oxidase showed the first hint of segregation into whisker-related patches. These patches were clear by P86. The evoked response at this age showed synaptic activity first in layer 4 and then in deep layer 5/upper layer 6. With maturity, responses became longer lasting with a complex sequence of synaptic activity at different cortical depths. The onset of functional activity is coincident with development of layer 4 and the onset of whisker-related pattern formation. A similar coincidence is seen in the rat, despite the markedly different chronological timetable, suggesting similar developmental mechanisms may operate in both species.

Spike-based synaptic plasticity and the emergence of direction selective simple cells: simulation results.

Direction selectivity (DS) of simple cells in the primary visual cortex was recently suggested to arise from short-term synaptic depression in thalamocortical afferents (Chance F, Nelson S, Abbott L (1998), J. Neuroscience 18(12): 4785-4799). In the model, two groups of afferents with spatially displaced receptive fields project through either depressing and non-depressing synapses onto the V1 cell. The degree of synaptic depression determines the temporal phase advance of the response to drifting gratings. We show that the spatial displacement and the appropriate degree of synaptic depression required for DS can develop within an unbiased input scenario by means of temporally asymmetric spike-timing dependent plasticity (STDP) which modifies both the synaptic strength and the degree of synaptic depression. Moving stimuli of random velocities and directions break any initial receptive field symmetry and produce DS. Frequency tuning curves and subthreshold membrane potentials akin to those measured for non-directional simple cells are thereby changed into those measured for directional cells. If STDP is such that down-regulation dominates up-regulation the overall synaptic strength adapts in a self-organizing way such that eventually the postsynaptic response for the non-preferred direction becomes subthreshold. To prevent unlearning of the acquired DS by randomly changing stimulus directions an additional learning threshold is necessary. To further protect the development of the simple cell properties against noise in the stimulus, asynchronous and irregular synaptic inputs are required.

Control of Serotonergic Function in Medial Prefrontal Cortex by Serotonin-2A Receptors through a Glutamate-Dependent Mechanism

We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.

Synaptic patterns of thalamocortical afferents in mouse barrels at postnatal day 11.

This study focuses on the synaptic output patterns of thalamocortical axons in mouse barrel cortex at postnatal day (P) 11. Axons were labeled by biotinylated dextran amine transported anterogradely following injection in vivo into the ventrobasal thalamus. Labeled axons in the posteromedial barrel subfield were examined by light and electron microscopy and then reconstructed in three dimensions to assess the spatial distribution of their synapses. Thalamocortical axons form asymmetrical synapses, both at varicosities and along cylindrical portions of the axons; usually, only one synapse occurs per site, contrasting with the case in the adult, in which multiple synapses are typical. At P11, varicosities without synapses are common. As in adult barrels, approximately 80% of synapses formed by thalamocortical axons are with dendritic spines; 20% are with dendritic shafts. The similarity in the distribution of thalamocortical synapses onto spines vs. dendrites in developing and mature barrels indicates that adult synaptic patterns already are specified at a very early stage of thalamocortical synaptogenesis.

Barrel Pattern Formation Requires Serotonin Uptake by Thalamocortical Afferents, and Not Vesicular Monoamine Release

Thalamocortical neurons innervating the barrel cortex in neonatal rodents transiently store serotonin (5-HT) in synaptic vesicles by expressing the plasma membrane serotonin transporter (5-HTT) and the vesicular monoamine transporter (VMAT2). 5-HTT knock-out (ko) mice reveal a nearly complete absence of 5-HT in the cerebral cortex by immunohistochemistry, and of barrels, both at P7 and adulthood. Quantitative electron microscopy reveals that 5-HTT ko affects neither the density of synapses nor the length of synaptic contacts in layer IV. VMAT2 ko mice, completely lacking activity-dependent vesicular release of monoamines including 5-HT, also show a complete lack of 5-HT in the cortex but display largely normal barrel fields, despite sometimes markedly reduced postnatal growth. Transient 5-HTT expression is thus required for barrel pattern formation, whereas activity-dependent vesicular 5-HT release is not.

Thalamo-cortical Afferents Control Transient Expression of the Dopamine D3 Receptor in the Rat Somatosensory Cortex

The D(3) dopamine receptor (D(3)R) is selectively and transiently expressed in the barrel neurons of the somatosensory cortex (SI) between the first and second postnatal weeks. The D(3)R expression starts after the initial ingrowth of thalamocortical afferents (TCAs) into the barrel cortex and could be induced or controlled by them. We show that unilateral electrolytic lesion of the thalamic ventrobasal complex immediately after birth leads to a decrease in the D(3)R mRNA concentration in the lesioned SI 7 days after the lesion, whereas the D(3)R binding is little affected. Fourteen days after the neonatal thalamic lesion, the D(3)R binding and mRNA are drastically reduced and the barrel-like pattern of the D(3)R is absent. Elevation of the D(3) binding normally seen between the first and second postnatal weeks does not occur. Thalamic lesion on P6 differentially affects the D(3)R expression. One day after the lesion, the D(3) binding and mRNA are down-regulated, but the effect is transient. Five days after the lesion the concentration of D(3) mRNA in the lesioned hemisphere returns to the control level. The typical barrel-like pattern of D(3)R expression is evident in the lesioned SI, although TCAs are completely absent. Quantitative analysis demonstrated elevated cellular levels of the D(3) mRNA in barrel neurons 5 days after the lesion. These higher levels are needed, perhaps, to support the increased production of the D(3)R protein appropriate for this age. Age-related dynamics of the D(3)R binding is retained in the lesioned SI, although the concentration of D(3)R sites remains reduced. These data demonstrate that intact thalamic input is essential for the formation of mechanisms responsible for developmental regulation of the D(3)R expression in the SI.

A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex

Activation of 5-hydroxytryptamine 2A (5-HT 2A) receptors by hallucinogenic drugs is thought to mediate many psychotomimetic effects including changes in affect, cognition and perception. Conversely, blockade of 5-HT 2A receptors may mediate therapeutic effects of many atypical antidepressant and antipsychotic drugs. The purpose of the present study was to determine the source of subcortical glutamatergic afferents, which would project widely throughout the anterior–posterior axis of the rat brain to the apical dendrites of layer V pyramidal cells of the medial prefrontal cortex, from which serotonin induces transmitter release via activation of 5-HT 2A receptors. Fiber-sparing chemical lesions of the medial thalamus selectively decreased the frequency of serotonin-induced excitatory postsynaptic currents recorded from layer V pyramidal cells in the prelimbic region of the medial prefrontal cortex by 60%. In contrast, large bilateral lesions of the amygdala did not alter the serotonin response. These thalamic lesions significantly decreased the amount of binding to either μ-opioid or metabotropic glutamate 2/3 receptors in the prelimbic region of the medial prefrontal cortex as expected from previous evidence that these agonists for these receptors suppress serotonin-induced excitatory postsynaptic currents by a presynaptic mechanism. Surprisingly, the amount of specific binding to cortical 5-HT 2A receptors was significantly increased by the medial thalamic lesions. Thus, these experiments demonstrate that activation of cortical 5-HT 2A receptors modulates transmitter release from thalamocortical terminals. Unexpectedly, lesioning the thalamocortical terminals also alters 5-HT 2A receptor binding in the prefrontal cortex. These findings are of interest with respect to understanding therapeutic effects of antidepressant/antipsychotic drugs and the known behavioral effects of thalamic lesions in humans.

Neither peripheral nerve input nor cortical NMDA receptor activity are necessary for recovery of a disrupted barrel pattern in rat somatosensory cortex

Elevating cortical serotonin (5-HT) in rats from postnatal day (P-) 0 to P-6 by administering the monoamine oxidase (MAO A) inhibitor, clorgyline, produces a dose-dependent spectrum of effects on rat somatosensory organization, ranging from enlarged with indistinct septa to a complete lack of vibrissae-related patterns. However, if clorgyline treatment is stopped on P-6, a qualitatively and quantitatively normal vibrissae-related pattern of thalamocortical afferents appears in somatosensory cortex (S-I) on P-10. We employed high performance liquid chromatography (HPLC), infraorbital nerve (ION) transection, N-methyl- d-aspartate (NMDA) receptor blockade, 1,1′-dioctadecyl-3,3,3″3′-tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic afferents, and CO histochemistry to determine whether peripheral nerve input and/or cortical NMDA receptor activity were required for the recovery of vibrissae-related patterns in clorgyline-treated animals. Clorgyline administration from P-0 to P-6 produced a 1589.4±53.3% increase in cortical 5-HT over control animals on P-6 and a 268.8±6.3% elevation over controls at P-10. Postnatal day 6 pups had significantly altered vibrissae-related patterns in S-I following 6 days of clorgyline treatment but by P-10, the characteristic vibrissae-related patterns were restored. Neither transection of the ION nor application of the NMDA antagonist, dl-2-amino-5-phosphonovaleric acid (APV), to the cortices of P-6 pups that were treated with clorgyline from birth had any significant effect on the recovery of the vibrissae-related patterns by P-10. These results indicate that neither peripheral nerve input nor cortical NMDA receptor activity are necessary for the restoration of cortical vibrissae-related patterns in rats that have sustained transient elevations of 5-HT.

Development and plasticity of cortical areas and networks.

The development of cortical layers, areas and networks is mediated by a combination of factors that are present in the cortex and are influenced by thalamic input. Electrical activity of thalamocortical afferents has a progressive role in shaping cortex. For early thalamic innervation and patterning, the presence of activity might be sufficient; for features that develop later, such as intracortical networks that mediate emergent responses of cortex, the spatiotemporal pattern of activity often has an instructive role. Experiments that route projections from the retina to the auditory pathway alter the pattern of activity in auditory thalamocortical afferents at a very early stage and reveal the progressive influence of activity on cortical development. Thus, cortical features such as layers and thalamocortical innervation are unaffected, whereas features that develop later, such as intracortical connections, are affected significantly. Surprisingly, the behavioural role of 'rewired' cortex is also influenced profoundly, indicating the importance of patterned activity for this key aspect of cortical function.

Differential Expression ofCOUP-TFI, CHL1,and Two Novel Genes in Developing Neocortex Identified by Differential Display PCR

Genes that control the specification and differentiation of the functionally specialized areas of the mammalian neocortex are likely expressed across the developing neocortex in graded or restricted patterns. To search for such genes we have performed a PCR-based differential display screen using RNAs from rostral neocortex, which included the primary motor area, and caudal neocortex, which included the primary visual area, of embryonic day 16 rats. We identified 82 differentially expressed gene fragments. Secondary screening by in situ hybridization confirmed that five fragments, representing four genes, are differentially expressed across developing rat neocortex. Two of the genes, chick ovalbumin upstream transcription factor I (COUP-TFI) and close homolog of L1 (CHL1), have been cloned previously, but their differential expression in cortex has not been reported. Sequences from the other two fragments suggest that they represent novel genes. The expression patterns include graded, restricted, and discontinuous expression with abrupt borders that might correlate with those of areas. The differential expression patterns of all four genes are established before the arrival of thalamocortical afferents, suggesting that they are independent of thalamic influence, and could direct or reflect arealization. In addition, COUP-TFI and CHL1 exhibit dynamic expression patterns that undergo substantial changes after thalamocortical afferents invade the cortical plate, suggesting that thalamic axons may influence their later expression. Postnatally, COUP-TFI is most prominently expressed in layer 4, in both rats and mice, and CHL1 is expressed in layer 5. COUP-TFI expression in cortex, and in ventral telencephalon and dorsal thalamus, suggests several possible causes for the loss of layer 4 neurons and the reduced thalamocortical projection reported in COUP-TFI knock-out mice.