77 research outputs found
Postnatal development of excitatory and inhibitory prefrontal cortical circuits and their disruption in autism
No full textThe prefrontal cortices, in particular lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC), have been implicated in top-down control of attention switching and behavioral flexibility. These cortices and their networks are disrupted in autism, a condition in which diverse behaviors such as social communication and attention control are dysregulated. However, little is known about the typical development of these cortical areas or the ways in which this process is altered in neurodevelopmental disorders. In order to identify changes that could affect the local processing of signals transmitted by the short-range pathways connecting the ACC and LPFC I assessed developmental changes in the distinct cortical layers, which send and receive different pathways and have unique inhibitory microenvironments that dictate excitatory-inhibitory balance. Normative developmental trends were compared with those seen in individuals with autism to identify changes that may contribute to symptoms of attention dysfunction. Unbiased quantitative methods were used to study overall neuron density, the density of inhibitory neurons labeled by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV), and the density, size, and trajectory of myelinated axons in the individual cortical layers in children and adults with and without a diagnosis of autism. There was a reduction in neuron density and an increase in the density of myelinated axons in both areas during neurotypical development. Axons in layers 1-3 of LPFC were disorganized in autism, with increased variability in the trajectory of axons in children and a decrease in the proportion of thin axons in adults. These findings were most significant in layer 1, the ultimate feedback-receiving layer in the cortex. While there were no differences in neuron populations between cohorts in children, in adults with autism there was a significant reduction in the density of CR-expressing neurons in LPFC layers 2-6 and a significant increase in the density of PV-expressing neurons in ACC layers 5-6. In autism, these findings suggest that dysregulation of the normal development of axonal networks, seen in children, may induce compensatory developmental changes in cell and axon populations in adults that could be connected to attention dysregulation.2021-10-07T00:00:00
Study of inhibitory neurons in Broca's area in autism
No full textIndividuals with Autism Spectrum Disorder (ASD) experience a variety of symptoms that vary dramatically across individuals and can range from severe impairments to minor issues with social interactions and communication. The underlying cause of ASD is still unknown, and the level of influence that genetic and environmental factors have on the severity and occurrence of ASD is still a topic of great debate. Since the theories concerning cause or causes of ASD are multifactorial, the treatment options available are extremely limited and are based on behavioral testing. Alternatively, genetic testing might be considered in a diagnosis protocol. This study is designed to investigate ASD by assessing the variability of three genes associated with neuronal inhibition. Based on previous studies this experiment hypothesized that GAD1, GAD2, and PAVLB expression is decreased in Broca’s area in individuals with ASD when compared to controls, with the premise that this alteration could contribute to the symptoms involving language and communication. In situ hybridization was used to quantify the expression of the GAD1, GAD2, and PVALB genes in Broca’s area in postmortem human tissue. The variability of these three genes was quantified by measuring the amount of radioactively tagged mRNA in fifty cell bodies in each brain sample. This study used twenty-two brains of individuals with ASD and twenty-one control brains, including age matched males and females. The variables of age and sex are analyzed and discussed as well as the emulsion and film analyses. A decrease in parvalbumin expression was found between the ASD and control groups in Broca’s area. These finding were discussed in the context of symptoms and neuropathological features of ASD
Parallel Driving and Modulatory Pathways Link the Prefrontal Cortex and Thalamus
No full textPathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling 'drivers' in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small 'modulatory' type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small 'modulatory' terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases.National Institute of Mental Health; National Institute of Neurological Disorders and Strok
Effects of distinct excitatory cortical and inhibitory reticular and local thalamic inputs on spindle dynamics
No full textBased on two distinct thalamocortical (TC) circuits with reciprocal components in
primates, we developed models of core, matrix, and mixed TC loops. The core TC circuit,
prevalent in sensory thalamus, drives activity focally in the middle cortical layers and gets
feedback through small modulatory cortical axon terminals from pyramidal neurons in layer 6
(L6). The matrix TC circuit, can drive activity in high-order thalamus, through large axon
terminals from cortical layer 5 (L5) pyramidal neurons and includes broad thalamic feedback to
the superficial cortical layers. The inhibitory thalamic reticular nucleus (TRN) intercepts all TC
communication and is situated strategically between the thalamus and cortex. We used distinct
core and matrix TRN components to engage cortico-TRN and thalamo-TRN loops in pure core,
pure matrix or mix TC loops to investigate the functional consequences of different ratios of core
and matrix node connectivity contribution to spindle dynamics. Our models comprised more
numerous projections from cortical L6 pyramidal neurons to TRN and thalamus, but we also
included direct L5 projections to matrix TRN (L5-TRN) and thalamus with a range of density of
L5-TRN, starting from zero. Based on our rate-based model circuit we found: a) increased local
inhibition in the thalamus or b) increased TRN inhibition of core and matrix thalamic neurons
enhances spindle generation and sustains spindle activity for longer periods; c) a more diffuse
nature of spindles in matrix compared to core, with the mix type showing intermediate properties
in agreement with hypotheses that spindles can be classified in core-generated, matrix-generated
or mixed types, depending on the neuroanatomy of pathways involved in their generation; d) the
involvement of L5-TRN projection enhances the spindle generation and propagation; and e)
spindle power can be modulated based on the level of cortical feedback and involvement in
model core vs. matrix. Our rate-based model tested the impact of different ratios and
specializations of neuroanatomical connectivity at multiple nodes of the TC circuit in spindle
dynamics. Our simulations provide detailed metrics for shifts in the engagement of distinct TRN,
core, and matrix circuits underlying typical sleep spindle generation and states of vigilance. This
work can help establish a framework to study disruption of TC-TRN circuit balance in seizures,
atypical sensory reactivity, and deficits in sleep and attentional gating seen in autism and
schizophrenia.Published versio
Sequential and parallel circuits for emotional processing in primate orbitofrontal cortex
No full textDoes layer 5 of the cortex project to the thalamic reticular nucleus? Implications for core and matrix thalamocortical circuits and sleep spindles
No full textTwo 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
Circuits for Multisensory Integration and Attentional Modulation Through the Prefrontal Cortex and the Thalamic Reticular Nucleus in Primates
No full textChanges in Prefrontal Axons May Disrupt the Network in Autism
No full textNeural communication is disrupted in autism by unknown mechanisms. Here, we examined whether in autism there are changes in axons, which are the conduit for neural communication. We investigated single axons and their ultrastructure in the white matter of postmortem human brain tissue below the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and lateral prefrontal cortex (LPFC), which are associated with attention, social interactions, and emotions, and have been consistently implicated in the pathology of autism. Area-specific changes below ACC (area 32) included a decrease in the largest axons that communicate over long distances. In addition, below ACC there was overexpression of the growth-associated protein 43 kDa accompanied by excessive number of thin axons that link neighboring areas. In OFC (area 11), axons had decreased myelin thickness. Axon features below LPFC (area 46) appeared to be unaffected, but the altered white matter composition below ACC and OFC changed the relationships among all prefrontal areas examined, and could indirectly affect LPFC function. These findings provide a mechanism for disconnection of long-distance pathways, excessive connections between neighboring areas, and inefficiency in pathways for emotions, and may help explain why individuals with autism do not adequately shift attention, engage in repetitive behavior, and avoid social interactions. These changes below specific prefrontal areas appear to be linked through a cascade of developmental events affecting axon growth and guidance, and suggest targeting the associated signaling pathways for therapeutic interventions in autism.</jats:p
A model for disruption and heterogeneity of attentional processes in autism: role of prefrontal cortical and thalamic networks
No full textPublished versio
A neural modeling approach to study mechanisms underlying the heterogeneity of visual spatial frequency sensitivity in schizophrenia
No full textPatients with schizophrenia exhibit abnormalities in spatial frequency sensitivity, and it is believed that these abnormalities indicate more widespread dysfunction and dysregulation of bottom-up processing. The early visual system, including the first-order Lateral Geniculate Nucleus of the thalamus (LGN) and the primary visual cortex (V1), are key contributors to spatial frequency sensitivity. Medicated and unmedicated patients with schizophrenia exhibit contrasting changes in spatial frequency sensitivity, thus making it a useful probe for examining potential effects of the disorder and antipsychotic medications in neural processing. We constructed a parameterized, rate-based neural model of on-center/off-surround neurons in the early visual system to investigate the impacts of changes to the excitatory and inhibitory receptive field subfields. By incorporating changes in both the excitatory and inhibitory subfields that are associated with pathophysiological findings in schizophrenia, the model successfully replicated perceptual data from behavioral/functional studies involving medicated and unmedicated patients. Among several plausible mechanisms, our results highlight the dampening of excitation and/or increase in the spread and strength of the inhibitory subfield in medicated patients and the contrasting decreased spread and strength of inhibition in unmedicated patients. Given that the model was successful at replicating results from perceptual data under a variety of conditions, these elements of the receptive field may be useful markers for the imbalances seen in patients with schizophrenia.5R01MH118500-05 REVISED - NIH/National Institute of Mental HealthFirst author draf
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