Biology subjects

McHugh, T. J.

Publications and source records attributed to McHugh, T. J..

9 recordsLinked to original sources

bioRxiv2026

Computational demands shape seizure susceptibility in recurrent neural networks

Brain areas differ in their inherent susceptibility to focal seizures, but the principles governing this risk remain unclear. While prior work has focused on anatomical and physiological factors, here we observed a fundamental contribution from the computations performed by the underlying neural network. Handcrafted and trained recurrent neural networks supporting continuous representations respond to seizure perturbations with higher activity and earlier performance decline relative to matched networks stabilizing discrete, well-separated states. Consistent with this prediction, in vivo recordings revealed that medial entorhinal cortex, whose grid cells exhibit continuous attractor dynamics, drives acute epileptiform discharges with stronger involvement and smoother state trajectories compared to CA3, a hippocampal subfield associated with discrete memory storage. Moreover, selective synaptic silencing demonstrated that this difference in seizure responses depends on intact entorhinal connectivity. Thus, the computations that enable neural networks to process information also influence their vulnerability to pathological transitions.

neuroscience↗

bioRxiv2024

Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced pain facilitation

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC[->]SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC[->]SDH-NAergic terminals causing the stress-induced pain hypersensitivity was 1A-adrenaline receptors (1ARs) in Hes5-positive (Hes5+) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5+ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A1-adenosine receptor (A1R)-knockdown in SDH-INs, and the A1R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC[->]SDH-NA neuronal signaling to Hes5+ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

neuroscience↗

bioRxiv2021

Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations

Chronic and acute stress differentially affect behaviour, as well as the structural integrity of the hippocampus, a key brain region involved in cognition and memory. However, it remains unclear if and how the facilitatory effects of acute stress on hippocampal information coding are disrupted as the stress becomes chronic. To examine this, we compared the impact of acute and chronic stress on neural activity in the CA1 subregion of male mice subjected to a chronic immobilization stress paradigm. We observed that following first exposure to stress (acute stress), the spatial information encoded in the hippocampus sharpened and the neurons became increasingly tuned to the underlying theta oscillation in the local field potential (LFP). However, following repeated exposure to same stress (chronic stress), spatial tuning was poorer and the power of both the slow-gamma (30-50 Hz) and fast-gamma (55-90 Hz) oscillations, which correlate with excitatory inputs into the region, decreased. These results support the idea that acute and chronic stress differentially affect neural computations carried out by hippocampal circuits and suggest that acute stress may improve cognitive processing.

neuroscience↗

bioRxiv2020

CA2 inhibition reduces the precision of hippocampal assembly reactivation

The structured reactivation of hippocampal neuronal ensembles during fast synchronous oscillatory events termed sharp-wave ripples (SWRs) has been suggested to play a crucial role in the storage and use of memory. Activity in both the CA2 and CA3 subregions can proceed this population activity in CA1 and chronic inhibition of either region alters SWR oscillations. However, the precise contribution of CA2 to the oscillation, as well as to the reactivation of CA1 neurons within it, remains unclear. Here we employ chemogenetics to transiently silence CA2 pyramidal cells in mice and observe that while SWRs still occur, the reactivation of CA1 pyramidal cell ensembles within the events lose both temporal and informational precision. These observations suggest that CA2 activity contributes to the fidelity of experience-dependent hippocampal replay.

neuroscience↗

bioRxiv2020

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. We found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). We found that parvalbumin-expressing basket cells as responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulates CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

neuroscience↗

bioRxiv2020

Stress enhances hippocampal neuronal synchrony and prolongs sharp-wave ripples

Chronic stress affects hippocampal function at multiple levels of neural organization. However, much of this understanding is derived from postmortem analyses of molecular, morphological, physiological and behavioral changes at fixed time points. Neural signatures of an ongoing stressful experience in the intact brain of awake animals and their links to later hippocampal dysfunction remain poorly understood. Here we used in vivo tetrode recordings to analyze the dynamic impact of 10 days of immobilization stress on neuronal activity in area CA1 of mice. Unexpectedly, there was a net decrease in pyramidal cell activity in stressed animals. Although these results suggest a lack of stress-induced hyperexcitability, more detailed analysis revealed that a greater fraction of spikes occurred specifically during sharp-wave ripples, resulting in an increase in neuronal synchrony. After repeated stress some of these alterations were visible during rest even in the absence of stress. These findings offer new insights into stress-induced alterations in ripple-spike interactions and mechanisms through which chronic stress may interfere with subsequent information processing.

neuroscience↗

bioRxiv2018

The hippocampus encodes delay and value information during delay-discounting decision making

The hippocampus, a region critical for memory and spatial navigation, has been implicated in delay discounting, the decline in subjective reward value when a delay is imposed. However, how delay discounting is encoded in the hippocampus is poorly understood. Here we recorded from the hippocampal CA1 region of mice performing a delay-discounting decision-making task, where delay lengths and reward amounts were changed across sessions, and identified subpopulations of neurons in CA1 which increased or decreased their firing rate during long delays. The activity of both delay-active and -suppressive cells reflected delay length, reward amount, and arm position, however manipulating reward amount differentially impacted the two populations, suggesting distinct roles in the valuation process. Further, genetic deletion of NMDA receptor in hippocampal pyramidal cells impaired delay-discount behavior and diminished delay-dependent activity in CA1. Our results suggest that distinct subclasses of hippocampal neurons concertedly support delay-discounting decision in a manner dependent on NMDA receptor function.

neuroscience↗

bioRxiv2017

BEHAVIORAL VARIABILITY AS A MEASURE OF SUBTLE PHENOTYPIC TRAIT EXPRESSION OF MOUSE EXECUTIVE FUNCTION DISTORTION

Task learning relies on brain executive function (EF), the construct of controlling and coordinating behavior under the everlasting flow of environmental changes. We have previously shown, that a complete knockout of a vertebrate brain-specific pair of gene paralogs (Ntng1/2) distorts the mouse EF, making behavior less predictable (more variable) via the affected working memory and attention (1). In the current study, conditionally targeting either serotonin transporter (5-HTT) or Emx1-expressing neurons, we show that the cell type-specific ablation of Ntng1 within the excitatory circuits of either cortex or thalamus does not have a profound impact on the EF but rather affects its certain modalities, i.e. impulsivity and/or selective attention, modulated by cognitive demand. Several mice of both conditional genotypes simultaneously occupy either top or bottom parameter-specific behavioral ranks, indicative of a subject-unique antagonistic either proficit or deficit of function within the same behavior. Employing genotype-attributable behavior variability as a phenotypic trait, we deduce, that Ntng1-parsed excitatory pathways contribute but do not fully reconstitute the attention-impulsivity phenotypes, associated with the mouse EF deficit. However, complete knockdown of Ntng1/2, and associated with it behavior variability, explains the deficit of executive function and task learning.

animal behavior and cognition↗

bioRxiv2017

Molecular Correlate Of Mouse Executive Function. Top-Down And Bottom-Up Information Flows Complementation By Ntng Gene Paralogs

Executive function (EF) is a regulatory construct of learning and general cognitive abilities. Genetic variations underlying the architecture of cognitive phenotypes are likely to affect EF and associated behaviors. Mice lacking one of Ntng gene paralogs, encoding the vertebrate brain-specific presynaptic Netrin-G proteins, exhibit prominent deficits in the EF control. Brain areas responsible for gating the bottom-up and top-down information flows differentially express Ntng1 and Ntng2, distinguishing neuronal circuits involved in perception and cognition. As a result, high and low cognitive demand tasks (HCD and LCD, respectively) modulate Ntng1 and Ntng2 associations either with attention and impulsivity (AI) or working memory (WM), in a complementary manner. During the LCD Ntng2supported neuronal gating of AI and WM dominates over the Ntng1-associated circuits. This is reversed during the HCD, when the EF requires a larger contribution of cognitive control, supported by Ntng1, over the Ntng2 pathways. Since human NTNG orthologs have been reported to affect human IQ (1), and an array of neurological disorders (2), we believe that mouse Ntng gene paralogs serve an analogous role but influencing brain executive functioning.

animal behavior and cognition↗