A minimal mechanistic model for temporal signal processing in the lateral geniculate nucleus

The receptive fields of cells in the lateral geniculate nucleus (LGN) are shaped by their diverse set of impinging inputs: feedforward synaptic inputs stemming from retina, and feedback inputs stemming from the visual cortex and the thalamic reticular nucleus. To probe the possible roles of these feedforward and feedback inputs in shaping the temporal receptive-field structure of LGN relay cells, we here present and investigate a minimal mechanistic firing-rate model tailored to elucidate their disparate features. The model for LGN relay ON cells includes feedforward excitation and inhibition (via interneurons) from retinal ON cells and excitatory and inhibitory (via thalamic reticular nucleus cells and interneurons) feedback from cortical ON and OFF cells. From a general firing-rate model formulated in terms of Volterra integral equations, we derive a single delay differential equation with absolute delay governing the dynamics of the system. A freely available and easy-to-use GUI-based MATLAB version of this minimal mechanistic LGN circuit model is provided. We particularly investigate the LGN relay-cell impulse response and find through thorough explorations of the model’s parameter space that both purely feedforward models and feedback models with feedforward excitation only, can account quantitatively for previously reported experimental results. We find, however, that the purely feedforward model predicts two impulse response measures, the time to first peak and the biphasic index (measuring the relative weight of the rebound phase) to be anticorrelated. In contrast, the models with feedback predict different correlations between these two measures. This suggests an experimental test assessing the relative importance of feedforward and feedback connections in shaping the impulse response of LGN relay cells.     

Development of spatial coarse-to-fine processing in the visual pathway

The sequential analysis of information in a coarse-to-fine manner is a fundamental mode of processing in the visual pathway. Spatial frequency (SF) tuning, arguably the most fundamental feature of spatial vision, provides particular intuition within the coarse-to-fine framework: low spatial frequencies convey global information about an image (e.g., general orientation), while high spatial frequencies carry more detailed information (e.g., edges). In this paper, we study the development of cortical spatial frequency tuning. As feedforward input from the lateral geniculate nucleus (LGN) has been shown to have significant influence on cortical coarse-to-fine processing, we present a firing-rate based thalamocortical model which includes both feedforward and feedback components. We analyze the relationship between various model parameters (including cortical feedback strength) and responses. We confirm the importance of the antagonistic relationship between the center and surround responses in thalamic relay cell receptive fields (RFs), and further characterize how specific structural LGN RF parameters affect cortical coarse-to-fine processing. Our results also indicate that the effect of cortical feedback on spatial frequency tuning is age-dependent: in particular, cortical feedback more strongly affects coarse-to-fine processing in kittens than in adults. We use our results to propose an experimentally testable hypothesis for the function of the extensive feedback in the corticothalamic circuit.     

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.     

Interdigitated paralemniscal and lemniscal pathways in the mouse barrel cortex

Primary sensory cortical areas receive information through multiple thalamic channels. In the rodent whisker system, lemniscal and paralemniscal thalamocortical projections, from the ventral posteromedial nucleus (VPM) and posterior medial nucleus (POm) respectively, carry distinct types of sensory information to cortex. Little is known about how these separate streams of activity are parsed and integrated within the neocortical microcircuit. We used quantitative laser scanning photostimulation to probe the organization of functional thalamocortical and ascending intracortical projections in the mouse barrel cortex. To map the thalamocortical projections, we recorded from neocortical excitatory neurons while stimulating VPM or POm. Neurons in layers (L)4, L5, and L6A received dense input from thalamus (L4, L5B, and L6A from VPM; and L5A from POm), whereas L2/3 neurons rarely received thalamic input. We further mapped the lemniscal and paralemniscal circuits from L4 and L5A to L2/3. Lemniscal L4 neurons targeted L3 within a column. Paralemniscal L5A neurons targeted a superficial band (thickness, 60 μm) of neurons immediately below L1, defining a functionally distinct L2 in the mouse barrel cortex. L2 neurons received input from lemniscal L3 cells and paralemniscal L5A cells spread over multiple columns. Our data indicate that lemniscal and paralemniscal information is segregated into interdigitated cortical layers.     

Ephrins regulate the formation of terminal axonal arbors during the development of thalamocortical projections

The development of connections between thalamic afferents and their cortical target cells occurs in a highly precise manner. Thalamic axons enter the cortex through deep cortical layers, then stop their growth in layer 4 and elaborate terminal arbors specifically within this layer. The mechanisms that underlie target layer recognition for thalamocortical projections are not known. We compared the growth pattern of thalamic explants cultured on membrane substrates purified from cortical layer 4, the main recipient layer for thalamic axons, and cortical layer 5, a non-target layer. Thalamic axons exhibited a reduced growth rate and an increased branching density on their appropriate target membranes compared with non-target substrate. When confronted with alternating stripes of both membrane substrates, thalamic axons grew preferentially on their target membrane stripes. Enzymatic treatment of cortical membranes revealed that growth, branching and guidance of thalamic axons are independently regulated by attractive and repulsive cues differentially expressed in distinct cortical layers. These results indicate that multiple membrane-associated molecules collectively contribute to the laminar targeting of thalamic afferents. Furthermore, we found that interfering with the function of Eph tyrosine kinase receptors and their ligands, ephrins, abolished the preferential branching of thalamic axons on their target membranes, and that recombinant ephrin-A5 ligand elicited a branch-promoting activity on thalamic axons. We conclude that interactions between Eph receptors and ephrins mediate branch formation of thalamic axons and thereby may play a role in the establishment of layer-specific thalamocortical connections.     

Characterization of factors regulating lamina-specific growth of thalamocortical axons

During development, most thalamocortical axons extend through the deep layers to terminate in layer 4 of neocortex. To elucidate the molecular mechanisms that underlie the formation of layer-specific thalamocortical projections, axon outgrowth from embryonic rat thalamus onto postnatal neocortical slices which had been fixed chemically was used as an experimental model system. When the thalamic explant was juxtaposed to the lateral edge of fixed cortical slice, thalamic axons extended farther in the deep layers than the upper layers. Correspondingly, thalamic axons entering from the ventricular side extended farther than those from the pial side. In contrast, axons from cortical explants cultured next to fixed cortical slices tended to grow nearly as well in the upper as in the deep layers. Biochemical aspects of lamina-specific thalamic axon growth were studied by applying several enzymatic treatments to the cortical slices prior to culturing. Phosphatidylinositol phospholipase C treatment increased elongation of thalamic axons in the upper layers without influencing growth in the deep layers. Neither chondroitinase, heparitinase, nor neuraminidase treatment influenced the overall projection pattern, although neuraminidase slightly decreased axonal elongation in the deep layers. These findings suggest that glycosylphosphatidylinositol-linked molecules in the cortex may contribute to the laminar specificity of thalamocortical projections by suppressing thalamic axon growth in the upper cortical layers.     

Characterization of factors regulating lamina‐specific growth of thalamocortical axons

During development, most thalamocortical axons extend through the deep layers to terminate in layer 4 of neocortex. To elucidate the molecular mechanisms that underlie the formation of layer‐specific thalamocortical projections, axon outgrowth from embryonic rat thalamus onto postnatal neocortical slices which had been fixed chemically was used as an experimental model system. When the thalamic explant was juxtaposed to the lateral edge of fixed cortical slice, thalamic axons extended farther in the deep layers than the upper layers. Correspondingly, thalamic axons entering from the ventricular side extended farther than those from the pial side. In contrast, axons from cortical explants cultured next to fixed cortical slices tended to grow nearly as well in the upper as in the deep layers. Biochemical aspects of lamina‐specific thalamic axon growth were studied by applying several enzymatic treatments to the cortical slices prior to culturing. Phosphatidylinositol phospholipase C treatment increased elongation of thalamic axons in the upper layers without influencing growth in the deep layers. Neither chondroitinase, heparitinase, nor neuraminidase treatment influenced the overall projection pattern, although neuraminidase slightly decreased axonal elongation in the deep layers. These findings suggest that glycosylphosphatidylinositol‐linked molecules in the cortex may contribute to the laminar specificity of thalamocortical projections by suppressing thalamic axon growth in the upper cortical layers. © 2000 John Wiley & Sons, Inc. J Neurobiol 42: 56–68, 2000     

Barrel cortex and whisker-mediated behaviors

Neural networks of the rodent barrel cortex are particularly tractable for developing a quantitative understanding of response transformations in a cortical column. A column in barrel cortex consists of approximately 10 compartments. Two thalamic input pathways, a sensory lemniscal one and sensorimotor paralemniscal one, are transformed to approximately 7 population outputs, each with distinct spatiotemporal response characteristics. Granular and supragranular layers are sites of segregated processing in lemniscal and paralemniscal pathways, whereas infragranular layers are sites of intracolumnar, lemniscal/paralemniscal integration. Individual thalamocortical connections are relatively weak, and a considerable fraction of thalamocortical afferents contributes to each sensory response. Intracortically, relatively few but strong synaptic connections contribute to sensory responses, and responses are rapidly terminated by inhibition. Overall cortical population activity is very low. Whiskers mediate a wide range of behaviors and many natural tactile behaviors occur very rapidly. Vibrissal object recognition can be size invariant and motion invariant and is based on the tactile 'Gestaltwahrnehmung' of shape.     

Modelling corticothalamic feedback and the gating of the thalamus by the cerebral cortex

Morphological studies have shown that excitatory synapses from the cortex constitute the major source of synapses in the thalamus. However, the effect of these corticothalamic synapses on the function of the thalamus is not well understood because thalamic neurones have complex intrinsic firing properties and interact through multiple types of synaptic receptors. Here we investigate these complex interactions using computational models. We show first, using models of reconstructed thalamic relay neurones, that the effect of corticothalamic synapses on relay cells can be similar to that of afferent synapses, in amplitude, kinetics and timing, although these synapses are located in different regions of the dendrites. This suggests that cortical EPSPs may complement (or predict) the afferent information. Second, using models of reconstructed thalamic reticular neurones, we show that high densities of the low-threshold Ca2+ current in dendrites can give these cells an exquisite sensitivity to cortical EPSPs, but only if their dendrites are hyperpolarized. This property has consequences at the level of thalamic circuits, where corticothalamic EPSPs evoke bursts in reticular neurones and recruit relay cells predominantly through feedforward inhibition. On the other hand, with depolarized dendrites, thalamic reticular neurones do not generate bursts and the cortical influence on relay cells is mostly excitatory. Models therefore suggest that the cortical influence can either promote or antagonize the relay of information, depending on the state of the dendrites of reticular neurones. The control of these dendrites may therefore be a determinant of attentional mechanisms. We also review the effect of corticothalamic feedback at the network level, and show how the cortical control over the thalamus is essential in co-ordinating widespread, coherent oscillations. We suggest mechanisms by which different modes of corticothalamic interaction would allow oscillations of very different spatiotemporal coherence to coexist in the thalamocortical system.     

Internal dynamics determine the cortical response to thalamic stimulation

Although spontaneous activity occurs throughout the neocortex, its relation to the activity produced by external or sensory inputs remains unclear. To address this, we used calcium imaging of mouse thalamocortical slices to reconstruct, with single-cell resolution, the spatiotemporal dynamics of activity of layer 4 in the presence or absence of thalamic stimulation. We found spontaneous neuronal coactivations corresponded to intracellular UP states. Thalamic stimulation of sufficient frequency (>10 Hz) triggered cortical activity, and UP states, indistinguishable from those arising spontaneously. Moreover, neurons were activated in identical and precise spatiotemporal patterns in thalamically triggered and spontaneous events. The similarities between cortical activations indicate that intracortical connectivity plays the dominant role in the cortical response to thalamic inputs. Our data demonstrate that precise spatiotemporal activity patterns can be triggered by thalamic inputs and indicate that the thalamus serves to release intrinsic cortical dynamics.     

Effects of alterations of the vibrissae-related organization of thalamocortical axons upon the organization and outgrowth of intracortical connections in the barrelfield of the rat

Previous studies have shown that intracortical projections in layer IV of the vibrissae representation of primary somatosensory cortex (S-I) are arrayed in a pattern complementary to that of thalamocortical axons (TCAs). Elevation of cortical serotonin (5-HT) in rats during the first postnatal week results in a transient disruption of the vibrissae-related pattern of TCAs and layer IV neurons in S-I. The present study examines the influence of elevated cortical 5-HT levels and the attendant loss of vibrissae-related TCA clusters on the organization of S-I intracortical connections. Cortical 5-HT was elevated in neonatal rats via chronic injections of clorgyline from birth until P-6. Animals were euthanized on P-6 or allowed to survive an additional 4 days without further clorgyline treatment. Distributions of TCAs and intracortical axons were assessed via application of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Di-I) and 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (Di-A) to the thalamic radiations and directly into the cortical barrelfield, respectively. Chronic administration of clorgyline resulted in a loss of the vibrissae-related organization of TCAs in layer IV of S-I. There was also a loss of the complementary pattern of intracortical projections in layer IV of this region. Discontinuation of clorgyline treatment resulted in a return of the vibrissae-related pattern of TCAs as well as the complementary pattern of intracortical projections. These results are consistent with the conclusion that the normal organization of intracortical projections in this region of S-I depends on the presence of the orderly array of TCAs.     

Effects of alterations of the vibrissae-related organization of thalamocortical axons upon the organization and outgrowth of intracortical connections in the barrelfield of the rat

Previous studies have shown that intracortical projections in layer IV of the vibrissae representation of primary somatosensory cortex (S-I) are arrayed in a pattern complementary to that of thalamocortical axons (TCAs). Elevation of cortical serotonin (5-HT) in rats during the first postnatal week results in a transient disruption of the vibrissae-related pattern of TCAs and layer IV neurons in S-I. The present study examines the influence of elevated cortical 5-HT levels and the attendant loss of vibrissae-related TCA clusters on the organization of S-I intracortical connections. Cortical 5-HT was elevated in neonatal rats via chronic injections of clorgyline from birth until P-6. Animals were euthanized on P-6 or allowed to survive an additional 4 days without further clorgyline treatment. Distributions of TCAs and intracortical axons were assessed via application of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Di-I) and 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (Di-A) to the thalamic radiations and directly into the cortical barrelfield, respectively. Chronic administration of clorgyline resulted in a loss of the vibrissae-related organization of TCAs in layer IV of S-I. There was also a loss of the complementary pattern of intracortical projections in layer IV of this region. Discontinuation of clorgyline treatment resulted in a return of the vibrissae-related pattern of TCAs as well as the complementary pattern of intracortical projections. These results are consistent with the conclusion that the normal organization of intracortical projections in this region of S-I depends on the presence of the orderly array of TCAs.     

Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators

Neuromodulators such as acetylcholine, serotonin, and noradrenaline are powerful regulators of neocortical activity. Although it is well established that cortical inhibition is the target of these modulations, little is known about their effects on GABA release from specific interneuron types. This knowledge is necessary to gain a mechanistic understanding of the actions of neuromodulators because different interneuron classes control specific aspects of excitatory cell function. Here, we report that GABA release from fast-spiking (FS) cells, the most prevalent interneuron subtype in neocortex, is robustly inhibited following activation of muscarinic, serotonin, adenosine, and GABA(B) receptors--an effect that regulates FS cell control of excitatory neuron firing. The potent muscarinic inhibition of GABA release from FS cells suppresses thalamocortical feedforward inhibition. This is supplemented by the muscarinic-mediated depolarization of thalamo-recipient excitatory neurons and the nicotinic enhancement of thalamic input onto these neurons to promote thalamocortical excitation.     

Somatosensory integration controlled by dynamic thalamocortical feed-forward inhibition

The temporal features of tactile stimuli are faithfully represented by the activity of neurons in the somatosensory cortex. However, the cellular mechanisms that enable cortical neurons to report accurate temporal information are not known. Here, we show that in the rodent barrel cortex, the temporal window for integration of thalamic inputs is under the control of thalamocortical feed-forward inhibition and can vary from 1 to 10 ms. A single thalamic fiber can trigger feed-forward inhibition and contacts both excitatory and inhibitory cortical neurons. The dynamics of feed-forward inhibition exceed those of each individual synapse in the circuit and are captured by a simple disynaptic model of the thalamocortical projection. The variations in the integration window produce changes in the temporal precision of cortical responses to whisker stimulation. Hence, feed-forward inhibitory circuits, classically known to sharpen spatial contrast of tactile inputs, also increase the temporal resolution in the somatosensory cortex.     

Enduring Effects of Early Life Stress on Firing Patterns of Hippocampal and Thalamocortical Neurons in Rats: Implications for Limbic Epilepsy

Early life stress results in an enduring vulnerability to kindling-induced epileptogenesis in rats, but the underlying mechanisms are not well understood. Recent studies indicate the involvement of thalamocortical neuronal circuits in the progression of kindling epileptogenesis. Therefore, we sought to determine in vivo the effects of early life stress and amygdala kindling on the firing pattern of hippocampus as well as thalamic and cortical neurons. Eight week old male Wistar rats, previously exposed to maternal separation (MS) early life stress or early handling (EH), underwent amygdala kindling (or sham kindling). Once fully kindled, in vivo juxtacellular recordings in hippocampal, thalamic and cortical regions were performed under neuroleptic analgesia. In the thalamic reticular nucleus cells both kindling and MS independently lowered firing frequency and enhanced burst firing. Further, burst firing in the thalamic reticular nucleus was significantly increased in kindled MS rats compared to kindled EH rats (p<0.05). In addition, MS enhanced burst firing of hippocampal pyramidal neurons. Following a stimulation-induced seizure, somatosensory cortical neurons exhibited a more pronounced increase in burst firing in MS rats than in EH rats. These data demonstrate changes in firing patterns in thalamocortical and hippocampal regions resulting from both MS and amygdala kindling, which may reflect cellular changes underlying the enhanced vulnerability to kindling in rats that have been exposed to early life stress.     

LTS and FS inhibitory interneurons, short-term synaptic plasticity, and cortical circuit dynamics

Somatostatin-expressing, low threshold-spiking (LTS) cells and fast-spiking (FS) cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS) pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates; the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime; LTS neurons protect against over-activation about as well as FS neurons.     

How are specific connections formed between thalamus and cortex?

During development precise thalamocortical connections are established, with reciprocal connections forming correctly in a laminar pattern as well as between the correct thalamic and cortical areas. Recent evidence suggests that both spatial and temporal cues may account for this specificity.     

Functional topography of corticothalamic feedback enhances thalamic spatial response tuning in the somatosensory whisker/barrel system

Corticothalamic (CT) projections are approximately 10 times more numerous than thalamocortical projections, yet their function in sensory processing is poorly understood. In particular, the functional significance of the topographic precision of CT feedback is unknown. We addressed these issues in the rodent somatosensory whisker/barrel system by deflecting individual whiskers and pharmacologically enhancing activity in layer VI of single whisker-related cortical columns. Enhancement of corticothalamic activity in a cortical column facilitated whisker-evoked responses in topographically aligned thalamic barreloid neurons, while activation of an adjacent column weakly suppressed activity at the same thalamic site. Both effects were more pronounced when stimulating the preferred, or principal, whisker than for adjacent whiskers. Thus, facilitation by homologous CT feedback sharpens thalamic receptive field focus, while suppression by nonhomologous feedback diminishes it. Our findings demonstrate that somatosensory cortex can selectively regulate thalamic spatial response tuning by engaging topographically specific excitatory and inhibitory mechanisms in the thalamus.     

Modeling absence seizure dynamics: implications for basic mechanisms and measurement of thalamocortical and corticothalamic latencies

A successful physiologically based continuum model of the corticothalamic system is applied to determine the relative contributions of axonal and intrinsic cellular delays to the waveforms of absence seizures. The predicted period of the absence seizure depends linearly on model parameters describing thalamocortical, corticothalamic, intracortical, and synaptodendritic delays, and these dependences are linked to the seizure mechanism by showing how time intervals between peaks in the waveforms depend on the parameters. Counterintuitively, it is found that a peak in the local field potential recorded in the thalamic relay nuclei can precede the peak in the cortical field that drove it, without violating causality, but rendering naive interpretation of time intervals between peaks invalid. We argue that a thalamocortical loop mechanism for absence seizures is consistent with intrathalamic cellular properties being the leading determinant of the frequency of spike-wave discharges in rat genetic models, with the combination of network and cellular properties providing a natural explanation for the lower frequency of human absence seizures. Finally, our results imply that the seizure frequency is not determined by the fastest thalamocortical and corticothalamic fibers, but rather depends on an effective weighted conduction velocity of all pathways present.     

Mechanisms Explaining Transitions between Tonic and Phasic Firing in Neuronal Populations as Predicted by a Low Dimensional Firing Rate Model

Several firing patterns experimentally observed in neural populations have been successfully correlated to animal behavior. Population bursting, hereby regarded as a period of high firing rate followed by a period of quiescence, is typically observed in groups of neurons during behavior. Biophysical membrane-potential models of single cell bursting involve at least three equations. Extending such models to study the collective behavior of neural populations involves thousands of equations and can be very expensive computationally. For this reason, low dimensional population models that capture biophysical aspects of networks are needed. The present paper uses a firing-rate model to study mechanisms that trigger and stop transitions between tonic and phasic population firing. These mechanisms are captured through a two-dimensional system, which can potentially be extended to include interactions between different areas of the nervous system with a small number of equations. The typical behavior of midbrain dopaminergic neurons in the rodent is used as an example to illustrate and interpret our results. The model presented here can be used as a building block to study interactions between networks of neurons. This theoretical approach may help contextualize and understand the factors involved in regulating burst firing in populations and how it may modulate distinct aspects of behavior.