Does layer 5 of the cortex project to the thalamic reticular nucleus? Implications for core and matrix thalamocortical circuits and sleep spindles

Two distinct thalamocortical (TC) circuits with reciprocal components can be identified in mammals: The core TC circuit, prevalent in sensory thalamus, drives activity focally in the middle cortical layers. In turn, these core thalamic neurons are innervated by small ‘modulatory’ cortical axon terminals from pyramidal neurons in layer 6(L6). The matrix TC circuit, prevalent in high-order thalamus, has a complementary organization: large axon terminals from cortical layer 5(L5) pyramidal neurons drive activity of matrix thalamic neurons that, in turn, innervate broadly and modulate the superficial cortical layers. Situated strategically between the thalamus and cortex, the inhibitory thalamic reticular nucleus (TRN) intercepts all TC communication. Projections from sensory or motor cortices to TRN terminate exclusively as small boutons and originate from L6, akin to core TC circuits. No studies have shown direct projections to TRN from cortical neurons in L5 that participate in matrix circuits. However, in comparison with other cortices, prefrontal cortices issue substantial projections to the thalamus from L5 and send similar driver-like projections to TRN, which terminate as large boutons and could potentially originate from L5. These large prefrontal axon terminals are similar to cortical boutons in the caudate nucleus and the amygdala, which originate mainly from L5. Based on this indirect evidence we tested the hypothesis that cortical L5 neurons project to TRN in matrix networks, by constructing a computational TC circuit that included core and matrix components with an optional cortical L5 to TRN projection (L5-TRN ON/OFF). Based on the features of TC circuits, our model was able to simulate relay and filtering of signals, and could initiate and propagate spindle oscillations. Activation of TRN neurons with L5-TRN ON in our model initiated spindle generation with different powers, depending on the level of cortical feedback and involvement of model core vs. matrix. Our preliminary findings are in agreement with hypotheses that spindles can be classified in core-generated, matrix-generated or mixed types, depending on the pathways involved in their generation, but only if L5-TRN is ON. Simulation results indicate a more diffuse nature of spindles in matrix compared to core, with the mix type showing intermediate properties, suggesting that shifts in the engagement of distinct TRN, core, and matrix circuits may underlie typical sleep spindle generation and states of vigilance. Disruption of TC-TRN circuit balance may underlie seizures, atypical sensory reactivity, and deficits in sleep and attentional gating seen in autism and schizophrenia.Accepted manuscrip

Visual attention deficits in schizophrenia can arise from inhibitory dysfunction in thalamus or cortex

Schizophrenia is associated with diverse cognitive deficits, including disorders of attention-related oculomotor behavior. At the structural level, schizophrenia is associated with abnormal inhibitory control in the circuit linking cortex and thalamus. We developed a spiking neural network model that demonstrates how dysfunctional inhibition can degrade attentive gaze control. Our model revealed that perturbations of two functionally distinct classes of cortical inhibitory neurons, or of the inhibitory thalamic reticular nucleus, disrupted processing vital for sustained attention to a stimulus, leading to distractibility. Because perturbation at each circuit node led to comparable but qualitatively distinct disruptions in attentive tracking or fixation, our findings support the search for new eye movement metrics that may index distinct underlying neural defects. Moreover, because the cortico-thalamic circuit is a common motif across sensory, association, and motor systems, the model and extensions can be broadly applied to study normal function and the neural bases of other cognitive deficits in schizophrenia.R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HHSPublished versio

The emotional gatekeeper: a computational model of attentional selection and suppression through the pathway from the amygdala to the inhibitory thalamic reticular nucleus

In a complex environment that contains both opportunities and threats, it is important for an organism to flexibly direct attention based on current events and prior plans. The amygdala, the hub of the brain's emotional system, is involved in forming and signaling affective associations between stimuli and their consequences. The inhibitory thalamic reticular nucleus (TRN) is a hub of the attentional system that gates thalamo-cortical signaling. In the primate brain, a recently discovered pathway from the amygdala sends robust projections to TRN. Here we used computational modeling to demonstrate how the amygdala-TRN pathway, embedded in a wider neural circuit, can mediate selective attention guided by emotions. Our Emotional Gatekeeper model demonstrates how this circuit enables focused top-down, and flexible bottom-up, allocation of attention. The model suggests that the amygdala-TRN projection can serve as a unique mechanism for emotion-guided selection of signals sent to cortex for further processing. This inhibitory selection mechanism can mediate a powerful affective 'framing' effect that may lead to biased decision-making in highly charged emotional situations. The model also supports the idea that the amygdala can serve as a relevance detection system. Further, the model demonstrates how abnormal top-down drive and dysregulated local inhibition in the amygdala and in the cortex can contribute to the attentional symptoms that accompany several neuropsychiatric disorders.R01MH057414 - NIMH NIH HHS; R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01NS024760 - NINDS NIH HHS; R01MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HH

A neural model of modified excitation/inhibition and feedback levels in schizophrenia

IntroductionThe strength of certain visual illusions, including contrast-contrast and apparent motion, is weakened in individuals with schizophrenia. Such phenomena have been interpreted as the impaired integration of inhibitory and excitatory neural responses, and impaired top–down feedback mechanisms.MethodsTo investigate whether and how these factors influence the perceived contrast-contrast and apparent motion illusions in individuals with schizophrenia, we propose a two-layer network, with top-down feedback from layer 2 to layer 1 that can model visual receptive fields (RFs) and their inhibitory and excitatory subfields.ResultsOur neural model suggests that illusion perception changes in individuals with schizophrenia can be influenced by altered top-down mechanisms and the organization of the on-center off-surround receptive fields. Alteration of the RF inhibitory surround and/or the excitatory center can replicate the difference of illusion precepts between individuals with schizophrenia within certain clinical states and normal controls. The results show that the simulated top-down feedback modulation enlarges the difference of the model illusion representations, replicating the difference between the two groups.DiscussionWe propose that the heterogeneity of visual and in general sensory processing in certain clinical states of schizophrenia can be largely explained by the degree of top-down feedback reduction, emphasizing the critical role of top-down feedback in illusion perception, and to a lesser extent on the imbalance of excitation/inhibition. Our neural model provides a mechanistic explanation for the modulated visual percepts of contrast-contrast and apparent motion in schizophrenia with findings that can explain a broad range of visual perceptual observations in previous studies. The two-layer motif of the current model provides a general framework that can be tailored to investigate subcortico-cortical (such as thalamocortical) and cortico-cortical networks, bridging neurobiological changes in schizophrenia and perceptual processing

Sleep spindles in primates: modelling the effects of distinct laminar thalamocortical connectivity in core, matrix, and reticular thalamic circuits

Sleep spindles are associated with the beginning of deep sleep and memory consolidation and are disrupted in schizophrenia and autism. In primates, distinct core and matrix thalamocortical (TC) circuits regulate sleep-spindle activity, through communications that are filtered by the inhibitory thalamic reticular nucleus (TRN) however, little is known about typical TC network interactions and the mechanisms that are disrupted in brain disorders. We developed a primate-specific, circuit-based TC computational model with distinct core and matrix loops that can simulate sleep spindles. We implemented novel multilevel cortical and thalamic mixing, and included local thalamic inhibitory interneurons, and direct layer 5 projections of variable density to TRN and thalamus to investigate the functional consequences of different ratios of core and matrix node connectivity contribution to spindle dynamics. Our simulations showed that spindle power in primates can be modulated based on the level of cortical feedback, thalamic inhibition, and engagement of model core vs. matrix, with the latter having a greater role in spindle dynamics. The study of the distinct spatial and temporal dynamics of core-, matrix-, and mix-generated sleep spindles establishes a framework to study disruption of TC circuit balance underlying deficits in sleep and attentional gating seen in autism and schizophrenia.5R01MH118500-05 REVISED - NIH/National Institute of Mental HealthFirst author draf

Homology of neocortical areas in rats and primates based on cortical type analysis: an update of the hypothesis on the dual origin of the neocortex

Sixty years ago, Friedrich Sanides traced the origin of the tangential expansion of the primate neocortex to two ancestral anlagen in the allocortex of reptiles and mammals, and proposed the Hypothesis on the Dual Origin of the Neocortex. According to Sanides, paraolfactory and parahippocampal gradients of laminar elaboration expanded in evolution by addition of successive concentric rings of gradually different cortical types inside the allocortical ring. Rodents had fewer rings and primates had more rings in the inner part of the cortex. In the present article, we perform cortical type analysis of the neocortex of adult rats, Rhesus macaques, and humans to propose hypotheses on homology of cortical areas applying the principles of the Hypothesis on the Dual Origin of the Neocortex. We show that areas in the outer rings of the neocortex have comparable laminar elaboration in rats and primates, while most 6-layer eulaminate areas in the innermost rings of primate neocortex lack homologous counterparts in rats. We also represent the topological distribution of cortical types in simplified flat maps of the cerebral cortex of monotremes, rats, and primates. Finally, we propose an elaboration of the Hypothesis on the Dual Origin of the Neocortex in the context of modern studies of pallial patterning that integrates the specification of pallial sectors in development of vertebrate embryos. The updated version of the hypothesis of Sanides provides explanation for the emergence of cortical hierarchies in mammals and will guide future research in the phylogenetic origin of neocortical areasThis work was supported by grants from the National Institute of Mental Health to BZ (Grant Nos. R01 MH101209 and R01 MH118500). MAG-C was the recipient of a Beatriz Galindo senior research position in the Faculty of Medicine at Universidad Autónoma de Madrid (BEAGAL18/00098) and of a Grant for I+D Projects by the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with Universidad Autónoma de Madrid in the line of action encouraging youth research doctors, in the context of the V PRICIT (Regional Program of Research and Technological Innovation), reference: SI2/PBG/2020-0001