Biology subjects

Mathur, B. N.

Publications and source records attributed to Mathur, B. N..

12 recordsLinked to original sources

bioRxiv2026

Anterior cingulate cortex activation of claustrum projection neuron subtypes is enhanced by alcohol

Cognitive impairment is a major component of Alcohol Use Disorder. Optimal cognitive performance requires anterior cingulate input activation of the claustrum, a subcortical nucleus that orchestrates cortical activity. Yet the impact of chronic alcohol exposure on the ability for the anterior cingulate cortex to drive activity of claustrum projection neuron subtypes is unknown. In adult male and female mice, we found that the majority of non-burst firing Type 1 claustrum projection neurons did not express the vesicular glutamate transporter 2 (VGLUT2), while the majority of burst firing Type 2 projection neurons were VGLUT2-expressing. Following chronic intermittent vaporized ethanol exposure (CIE), we found that both Type 1 and VGLUT2-non-expressing neurons exhibited increased responsivity to anterior cingulate cortex input activation that was mediated by increased postsynaptic membrane excitability. In contrast, Type 2 and VGLUT2-expressing projection neurons exhibited increased responsivity to anterior cingulate cortex input due to strengthened pre- and post-synaptic transmission mechanisms. Altogether, we uncovered a hyper-excitatory drive of the claustrum by the anterior cingulate cortex following chronic alcohol exposure. The data provide a foundational resource for the complex effects of chronic alcohol exposure on the claustrum, a critical cognitive control nucleus.

neuroscience↗

bioRxiv2025

Perineuronal Net and Inhibitory Synapse Remodeling on Striatal Fast-spiking Interneurons by Chronic Alcohol Exposure

Alcohol use disorder is characterized by persistent drinking in the face of negative consequences. Such inflexible drinking requires dorsolateral striatum fast-spiking interneurons, which comprise roughly 1% of all striatal neurons. How chronic ethanol exposure affects fast-spiking interneuron physiology is poorly understood. We discover in mice that chronic ethanol exposure induced a dramatic loss of GABAergic, but not glutamatergic, synapses onto dorsolateral striatum fast-spiking interneuron somata and proximal dendrites where perineuronal nets, a subdivision of the extracellular matrix, are enriched. We found that chronic ethanol exposure degraded these perineuronal nets and that enzymatically degrading perineuronal nets similarly reduced GABAergic transmission onto dorsolateral striatum fast-spiking interneurons. Modeling the effect of alcohol, we find that silencing extrinsic GABAergic projections to the dorsolateral striatum increased voluntary ethanol consumption. Taken together, these data suggest chronic alcohol exposure remodels perineuronal nets and inhibitory synapses on fast-spiking interneurons to facilitate alcohol drinking.

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bioRxiv2025

Dopamine receptor 1 specific CRISPRa mice exhibit disrupted behaviors and striatal baseline cellular activity

The two main cell types in the striatum, dopamine receptor 1 and adenosine receptor 2a spiny projection neurons (D1-SPNs and A2A-SPNs), have distinct roles in regulating motor- and reward-related behaviors. Cre-selective CRISPR-dCas9 systems allow for cell-type specific, epigenomic-based manipulation of gene expression with gene-specific single guide RNAs (sgRNAs) and have potential to elucidate molecular mechanisms underlying striatal subtype mediated behaviors. Conditional transgenic Rosa26:LSL-dCas9-p300 mice were recently generated to allow for robust expression of dCas9-p300 expression with Cre-driven cell-type specificity. This system utilizes p300, a histone acetyltransferase which regulates gene expression by unwinding chromatin and making that region of the genome more accessible for transcription. Rosa26-LSL-dCas9-p300 mice were paired with Drd1-Cre and Ador2a-Cre mice to generate Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 mouse lines and underwent behavioral phenotyping when sgRNAs were not present. Both Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 have cell-type specific expression of spCas9 mRNA. Baseline behavioral assessments revealed that, under a sgRNA absent nontargeted state, Drd1-Cre:dCas9-p300 mice display repetitive spinning behavior, hyperlocomotion and enhanced acquisition of reward learning in comparison to all genotypic littermates. In contrast, Ador2a-Cre:dCas9-p300 do not exhibit any changes in behavior in comparison to their littermates. Electrophysiological recordings of dorsal striatum D1-SPNs revealed that Drd1-Cre:dCas9-p300 mice have increased input resistance and increased spontaneous excitatory postsynaptic current amplitude, together suggesting greater excitatory drive of D1-SPNs. Overall, these data demonstrate the necessity to validate CRISPR-dCas9 lines for research investigations. Additionally, the Drd1-Cre:dCas9-p300 line has the potential to be used to study underlying mechanisms of stereotypy and reward-learning. Significance StatementUsing CRISPR-based tools to identify cell-type specific epigenomic and transcriptional mechanisms in disease and behavior has high utility for the neuroscience field. Previous limitations related to implementation of CRISPR-editing systems in mice were thought to be overcome by the generation of transgenic mouse lines, including a novel Cre-dependent dCas9-p300 mouse line. Our data shows however that Drd1-Cre:dCas9-p300 mice, generated from breeding Drd1-Cre mice with the dCas9-p300 mice, have cellular and behavioral disruptions under a nontargeted sgRNA absent state. Overall, these data suggest caution in employing CRISPR-dCas9 systems, particularly transgenic mouse lines, for research investigations.

neuroscience↗

bioRxiv2025

The human claustrum initiates networks for externally and internally driven task demands.

Cognitive control is believed to arise from interactions among multiple brain networks depending on task demands. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Because the claustrum possesses widespread connections with cortex and can synchronize distant cortical regions, we tested whether the claustrum activates task-dependent network states using fMRI during working memory (n = 420) and autobiographical memory (n = 35), tasks which elicit opposing responses from key cognitive control networks. In both tasks, the claustrum exhibited increased activity and excitatory influence on task-associated cognitive control network nodes, with corroborating underlying structural connectivity. The claustrum also displayed stronger excitatory effective connectivity during task performance and greater structural connectivity with task-related network nodes than regions prominently implicated in directing network states--the anterior insula and pulvinar. These findings establish a role for the claustrum in initiating network states for cognitive control. SignificanceCognitive functioning is supported by large-scale networks across the brain. Yet, the neural circuit mechanisms supporting task-dependent network activation are largely unknown. Circuit analyses using human functional and structural neuroimaging in this study found that the claustrum, a subcortical nucleus, activates during multiple cognitive tasks eliciting a wide range of network states, possesses strong anatomical connections with cognitive control network nodes, and exerts excitatory influence on task-associated network regions. These results establish the claustrum as a network activator subserving cognitive control.

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bioRxiv2024

The human claustrum activates across multiple cognitive tasks

Cognitive control, the ability to manage information during purposeful actions, is crucial for everyday functioning and can become impaired in a variety of neuropsychiatric disorders. The claustrum, a subcortical brain structure, has recently been implicated in functional mechanisms underlying cognitive control. A current theory on the claustrums function, the Network Instantiation in Cognitive Control (NICC) model, proposes that the claustrum acts as a cortical network hub synchronizing distant parts of the brain to optimize task performance across cognitive domains. Testing this in this study, we examined the claustrum signal within a dataset (n = 55) that includes functional MRI (fMRI) of healthy participants engaged in four well-established cognitive tasks: the Stroop task, AX-continuous performance task (AX-CPT), cued task-switching, and Sternberg working memory task. Bilateral claustrum activation was observed during certain conditions and trial phases of all four tasks, particularly during active use of cognitive control, and coinciding with task-positive cortical network activations. These findings provide further support for the NICC model of claustrum function, demonstrating claustrum activation across multiple cognitive tasks, and potentially paving the way for new insights into how cognitive processes can become compromised in neuropsychiatric disorders.

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bioRxiv2023

Modeling an ultra-rare epilepsy variant in wildtype mice with in utero prime editing

Generating animal models that mirror a patients seizures within clinically-useful timeframes is an important step toward advancing precision medicine for genetic epilepsies. Here we report a somatic cell genome editing approach that rapidly incorporated a patients genomic variant into mice, which developed seizures recapitulating elements of the patients pathology. This approach offers a versatile in vivo platform for clinical, preclinical, and basic research applications, including tailoring pharmacotherapy, assessing variants of uncertain significance, and screening compounds to develop drugs for rare epilepsies. As proof-of-principle, we modeled an epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A using prime editing in utero directly in the developing brain of wild-type mice. This methodology achieved high-fidelity genome editing in vivo sufficient to induce frequent spontaneous seizures without necessitating germline modification or extensive breeding. Leveraging the speed and versatility of this approach, we propose a generalizable workflow to generate bedside-to-bench animal models of individual patients within weeks. This advance holds promise for providing a cost-effective, expedient in vivo testing platform that reduces barriers to access for precision medicine, and accelerates drug development for rare and neglected neurological conditions.

neuroscience↗

bioRxiv2023

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

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bioRxiv2022

The rostral intralaminar nuclear complex of the thalamus supports striatally-mediated action reinforcement

The dorsal striatum (DS) mediates the selection of actions for reward acquisition necessary for survival. Striatal pathology contributes to several neuropsychiatric conditions, including aberrant selection of actions for specific rewards in addiction. A major source of glutamate driving striatal activity is the rostral intralaminar nuclei of the thalamus (rILN). Yet, the information that is relayed to the striatum to support action selection is unknown. Here we discovered that rILN neurons projecting to the DS integrated information from several subcortical and cortical sources and that these rILN[->]DS neurons stably signaled at two time points in mice performing an action sequence task reinforced by sucrose reward: action initiation and reward acquisition. In vivo activation of this pathway increased the number of successful trials whereas inhibition decreased the number of successful trials. These findings illuminate a role for the rostral intralaminar nuclear complex in reinforcing actions.

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bioRxiv2022

The mouse claustrum synaptically connects cortical network motifs

Spatially distant areas of cerebral cortex coordinate their activity into networks that are integral to cognitive processing. A common structural motif of cortical networks is co-activated frontal and posterior cortical regions. Knowledge of the neural circuit mechanisms underlying such widespread inter-areal cortical coordination is lacking. Using anesthetized mouse functional magnetic resonance imaging (fMRI) we discovered that mouse frontal cortical functional connectivity reflects the common cortical network motif in its functional connectivity to posterior cortices, but also demonstrates significant functional connectivity with the claustrum. Exploring whether the claustrum may synaptically support such network architecture, we used a channelrhodopsin-assisted electrophysiological circuit mapping approach to assess the strength of synaptic connectivity of 35 unique frontal cortico-claustral-cortical connections through 1,050 subtype-identified claustrum projection neurons. We observed significant trans-claustral synaptic connectivity from the anterior cingulate cortex and prelimbic prefrontal cortex back to originating frontal cortical regions as well as to posteriorly-lying visual and parietal association cortices contralaterally. The infralimbic prefrontal cortex possessed significant trans-claustral synaptic connectivity with the posteriorly-lying retrosplenial cortex, but to a far lesser degree with visual and parietal association cortices. These data reveal discrete extended cortical pathways through the claustrum that are positioned to support cortical network motifs central to cognitive control functions.

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bioRxiv2022

Estradiol mediates stress-susceptibility in the male brain

In susceptible populations, stress is a major risk factor for the development of mental disorders, including depression. Estradiol, often considered a female hormone, is distributed in the male brain via aromatization of testosterone. The role of estrogen receptors (ERs) in male stress susceptibility and depression is not well understood. We found that absence of ER{beta} is associated with susceptibility to stress in male mice and that activity of ER{beta}-projecting neurons from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive behaviors. We identified that absence of estradiol, but not testosterone per se, underlies stress susceptibility and that brain-selective delivery of estradiol prevents the development of depression-related behaviors. Our findings provide evidence for an estrogen-based mechanism underlying stress susceptibility and offer an unexpected therapeutic strategy for treating depression in males.

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bioRxiv2018

The human claustrum is functionally connected to cognitive networks and involved in cognitive control

The claustrum is among the most highly connected structures in the mammalian brain. However, the function of the claustrum is unknown, which is due to its peculiar anatomical arrangement. Here, we use resting state and task functional magnetic resonance imaging (fMRI) to elucidate claustrum function in human subjects. We first describe a method to reveal claustrum signal with no linear relationship with adjacent regions. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n=20) and a separate 3T dataset for replication (n=35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n=33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, the claustrum was significantly activated at the onset of the difficult condition of the task, but not during the remainder of the difficult condition. These data suggest that the claustrum can be functionally isolated with fMRI, and that it is involved in cognitive control in humans independent of sensorimotor processing.\n\nHighlightsO_LIRemoving signal from neighboring structures isolates claustrum BOLD signal at 7T and 3T field strength\nC_LIO_LIClaustrum is extensively functionally connected with cortex, including cognitive networks\nC_LIO_LIClaustrum is activated at the onset of a cognitive conflict task\nC_LIO_LIClaustrum may be involved in cognition independent of sensorimotor processing\nC_LI

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bioRxiv2018

The claustrum is required for reward acquisition under high cognitive demand

The claustrum is proposed to mediate a variety of functions ranging from sensory binding to top-down cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking. Here we employ the guanine nucleotide-binding subunit beta-4 cre driver line in mice to selectively monitor and manipulate claustrum projection neurons. Using fiber photometry, we find elevated claustrum activity prior to an expected cue during correct performance on a cognitively demanding five-choice response assay relative to a less-demanding one-choice version of the task. Claustrum activity during reward acquisition is also enhanced when cognitive demand is higher. Furthermore, we use optogenetic inhibition of claustrum prior to the expected cue to demonstrate that claustrum is critical for accurate performance on the five-choice, but not the one-choice, task. These results suggest the claustrum supports a cognitive control function necessary for reward acquisition under cognitively demanding conditions.

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