Biology subjects

Hallock, H. L.

Publications and source records attributed to Hallock, H. L..

9 recordsLinked to original sources

bioRxiv2025

Shifts in attentional demand are accompanied by sex-specific patterns of insula-frontal cortical interactions in mice

The insula is a brain region that is correlated with the cognitive process of attention in humans. Aberrant insula function is also implicated in attentional impairments in several psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia. Although the insulas role in attention has been well-studied in humans, we do not yet have an understanding of how the insula communicates with other brain areas to promote attentional processing. Here, we show that neurons in the mouse insula send direct axonal projections to the frontal cortex, and that these two brain areas functionally interact in different ways between male and female mice performing a touchscreen-based attention task. Specifically, we recorded and analyzed local field potentials (LFPs) from the insula and frontal cortex while mice performed variants of a rodent analogue of the continuous performance test of attention, or rCPT. In male mice, we found that activity in the frontal cortex preceded insular activity when the task was well-learned, but that insula-frontal cortex synchrony decreased when the need to inhibit responding was high. In female mice, synchrony between the insula and frontal cortex was largely bidirectional, but was high during all session types. We further demonstrate that patterns of theta-gamma coupling between the frontal cortex and insula distinguish between correct choices and errors during the rCPT, and that these patterns diverge between sexes. Our results suggest that functional differences in insula-frontal cortical circuitry at least partially underlie sex differences in attention-guided behavior in mice. HighlightsO_LIWe measured local field potentials (LFPs) in the mouse insula and frontal cortex during a translationally-relevant touchscreen-based task of attention C_LIO_LIManipulation of stimulus frequency during the task increased the demand on vigilance and response inhibition C_LIO_LIIn male mice, frontal cortex-driven synchrony in slow frequency bands reflected task rules, while theta-gamma coupling reflected errors when demand on response inhibition was increased C_LIO_LIIn female mice, bidirectionally-driven synchrony in slow frequency bands also reflected task rules, while theta-gamma coupling reflected errors when demand on vigilance was increased C_LI

neuroscience↗

bioRxiv2024

Overexpression of the Apoe gene in the frontal cortex of mice causes sex-dependent changes in learning, attention, and anxiety-like behavior

Apolipoprotein E (ApoE) is a protein that is important for lipid storage, transport, and metabolism. APOE gene variants are associated with Alzheimers disease (AD), as well as attentional function in healthy humans. Previous research has shown that Apoe transcription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests that Apoe may affect attentional function by virtue of its expression in circuits that control attention. Does Apoe causally regulate attention, or is its expression simply a byproduct of neuronal activity in the LC and FC? To answer this question, we synthetically induced Apoe transcription in the FC of male and female mice, and subsequently tested their ability to learn a touchscreen-based rodent version of the continuous performance test of sustained attention (the rCPT). We found that increased Apoe transcription impaired performance when attentional demand was increased in male mice, while in female mice, increased Apoe transcription significantly accelerated rCPT learning. We further found that this increase in Apoe transcription affected subsequent anxiety-like behavior and cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into how Apoe causally regulates translationally relevant behaviors in rodent models.

neuroscience↗

bioRxiv2024

Stimulation of locus coeruleus inputs to the frontal cortex in mice induces cell type-specific expression of the Apoe gene

Deficits in attention are common across a range of neuropsychiatric disorders. A multitude of brain regions, including the frontal cortex (FC) and locus coeruleus (LC), have been implicated in attention. Regulators of these brain regions at the molecular level are not well understood, but might elucidate underlying mechanisms of disorders with attentional deficits. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the FC, and subsequent bulk RNA-sequencing from the mouse FC. We found that stimulation of this circuit caused an increase in transcription of the Apoe gene. To investigate cell type-specific expression of Apoe in the FC, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the FC, or a control virus, and found that increases in Apoe expression in the FC following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in cortical microcircuits that are important for attention-guided behavior, and point to interneuron-specific expression of Apoe as a potential target for the amelioration of attention symptoms in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimers disease (AD). Significance StatementIdentifying patterns of gene expression in specific brain circuits is an important first step toward developing treatments for cognitive and behavioral symptoms that rely on those circuits. In this paper, we describe a transcriptome-scale motif in one such circuit - neurons in the LC that project to the FC. This circuit has been implicated in attention, and attentional deficits are common across many neuropsychiatric disorders, suggesting that targeting this circuit could have therapeutic potential for ameliorating attentional symptoms in these disorders. We further explored one of the top differentially expressed genes, Apoe, to identify how it is expressed in distinct cell types following stimulation of this circuit, paving the way for spatially- and genetically-specific targeting of this gene in attention.

genetics↗

bioRxiv2023

Electrophysiological correlates of attention in the locus coeruleus - anterior cingulate cortex circuit during the rodent continuous performance test

Sustained attention, the ability to focus on an activity or stimulus over time, is significantly impaired in many psychiatric disorders, and there remains a major unmet need in treating impaired attention. Continuous performance tests (CPTs) were developed to measure sustained attention in humans, non-human primates, rats, and mice, and similar neural circuits are engaged across species during CPT performance, supporting their use in translational studies to identify novel therapeutics. Here, we identified electrophysiological correlates of attentional performance in a touchscreen-based rodent CPT (rCPT) in the locus coeruleus (LC) and anterior cingulate cortex (ACC), two inter-connected regions that are implicated in attentional processes. We used viral labeling and molecular techniques to demonstrate that neural activity is recruited in LC-ACC projections during the rCPT, and that this recruitment increases with cognitive demand. We implanted male mice with depth electrodes within the LC and ACC for local field potential (LFP) recordings during rCPT training, and identified an increase in ACC delta and theta power, and an increase in LC delta power during correct responses in the rCPT. We also found that the LC leads the ACC in theta frequencies during correct responses while the ACC leads the LC in gamma frequencies during incorrect responses. These findings may represent translational biomarkers that can be used to screen novel therapeutics for drug discovery in attention.

neuroscience↗

bioRxiv2023

Harnessing prefrontal-hippocampal theta synchrony to enhance memory-guided choice

Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6-11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain machine interface that initiated task trials based on the magnitude of prefrontal hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain machine interfacing.

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bioRxiv2021

Expression of brain-derived neurotrophic factor in basolateral amygdala inputs to lateral septum is necessary for mice to identify socially novel individuals

The lateral septum (LS) is a GABAergic region in the basal forebrain that is implicated in sociability. However, the neural circuits and cell signaling pathways that converge on the LS to mediate social behaviors arent well understood. Multiple lines of evidence suggest that brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays important roles in social behavior. While BDNF is not locally produced in LS, we demonstrate that nearly all GABAergic neurons in LS express TrkB. Local knock-down of TrkB expression from LS neurons decreased sociability and reduced recruitment of social novelty-induced neural activity. Since BDNF is not synthesized in LS, we evaluated which inputs to the LS could serve as potential BDNF sources for controlling sociability. By selectively ablating inputs to LS, we demonstrated that inputs from the basolateral amygdala (BLA), but not ventral CA1 (vCA1), regulate sociability. Moreover, depleting BDNF selectively in BLA-LS projection neurons phenocopied the decreased sociability observed following either local LS TrkB knockdown or ablation of BLA-LS inputs. These data support the hypothesis that BLA-LS projection neurons could serve as a critical source of BDNF for activating TrkB signaling in LS neurons to control sociability.

neuroscience↗

bioRxiv2021

Stimulus degradation impairs performance in a rodent continuous performance test

Sustained attention is a core cognitive domain that is often disrupted in neuropsychiatric disorders. Continuous performance tests (CPTs) are the most common clinical assay of sustained attention. In CPTs, participants produce a behavioral response to target stimuli and refrain from responding to non-target stimuli. Performance in CPTs is measured as the ability to discriminate between targets and non-targets. Rodent versions of CPTs (rCPT) have been developed and validated with both anatomical and pharmacological studies, providing a translational platform for understanding the neurobiology of sustained attention. In human studies, using degraded stimuli (decreased contrast) in CPTs impairs performance and patients with schizophrenia experience a larger decrease in performance compared to healthy controls. In this study, we tested multiple levels of stimulus degradation in a touchscreen version of the CPT in mice. We found that stimulus degradation significantly decreased performance in both males and females. The changes in performance consisted of a decrease in stimulus discrimination, measured as d, and increases in hit reaction time and reaction time variability. These findings are in line with the effects of stimulus degradation in human studies. Overall, female mice demonstrated a more liberal response strategy than males, but response strategy was not affected by stimulus degradation. These data extend the utility of the mouse CPT by demonstrating that stimulus degradation produces equivalent behavioral responses in mice and humans. Therefore, the degraded stimuli rCPT has high translational value as a preclinical assay of sustained attention.

neuroscience↗

bioRxiv2021

The Ventral Midline Thalamus Mediates Successful Deliberation by Coordinating Prefrontal and Hippocampal Neural Activity

When faced with difficult choices, the possible outcomes are considered through a process known as deliberation. In rats, deliberation can be reflected by pause-and-reorienting behaviors, better known as Vicarious Trial and Errors (VTEs). While VTEs are thought to require medial prefrontal cortex (mPFC) and dorsal hippocampal (dHPC) interactions, no work has demonstrated such a dual requirement. The nucleus reuniens (Re) of the ventral midline thalamus is anatomically connected with both the mPFC and dHPC, is required for HPC-dependent spatial memory tasks, and is critical for mPFC-dHPC neural synchronization. Currently, it is unclear if, or how, the Re is involved in deliberation. Therefore, by examining the role of the Re on VTE behaviors, we can better understand the anatomical and physiological mechanisms supporting deliberation. Here, we examined the impact of Re suppression on VTE behaviors and mPFC-dHPC theta synchrony during well-learned performance of a HPC-dependent delayed alternation (DA) task. Pharmacological suppression of the Re increased VTE behaviors that resulted in erroneous choices. These errors were best characterized as perseverative behaviors, where at the decision-point, some rats repeatedly turned in the direction that previously yielded no reward, while simultaneously deliberating. These failed deliberations were associated with a reduction in mPFC-dHPC theta coherence at the choice-point. Importantly, the reduction in mPFC-dHPC theta synchrony observed during VTE behaviors was almost entirely driven by Re-suppression induced changes to the mPFC theta oscillation. Our findings suggest that the Re is important for successful deliberation, and mPFC-dHPC interactions, by coordinating local theta oscillations in the mPFC.

neuroscience↗

bioRxiv2019

Bdnf promoter IV-expressing cells in the hippocampus modulate fear expression and hippocampal-prefrontal synchrony in mice

Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To understand how promoter IV-derived BDNF affects fear expression and HC-PFC connectivity, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts ("p4-cells") for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ERT2CreERT2-PEST). Using this construct, we found that ventral (vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically-defined cell types that selectively contribute to BDNF-dependent behaviors.

neuroscience↗