Biology subjects

McAllister, B. B.

Publications and source records attributed to McAllister, B. B..

8 recordsLinked to original sources

bioRxiv2025

DISTINCT NEURAL SIGNATURES OF HIPPOCAMPAL POPULATION DYNAMICS DURING LOCOMOTION-IN-PLACE

Hippocampal CA1 neurons modulate their activity with movement variables such as time, distance, and speed, yet it remains unclear how these representations reorganize across behavioral states, from externally driven to self-paced movement and immobility. Here, we investigated how sensory events that initiate or terminate locomotion, structure CA1 population codes and how these codes reorganize across sensory-driven locomotion, spontaneous locomotion, and forced immobility. Using two-photon calcium imaging in head-fixed Thy1-GCaMP mice (n = 5) performing the air-induced running task on a non-motorized conveyor belt, we examined neuronal firing-rate modulation across a series of behavioral configurations designed to probe distinct forms of locomotion-in-place. In the No-Brake (locomotion-permitted) condition, the belt rotated freely, allowing animals to execute full cyclic limb movements in response to air stimulation. In the Brake (immobility) condition, the belt was fixed, restricting movement to partial or attempted locomotor motions. Firing-rate modulation with respect to time, distance, and speed was quantified using linear (Pearson correlation) and nonlinear (mutual information) metrics under permutation testing in the natural reference domains. Behaviorally, air stimuli produced faster, sustained running during air-on and more variable, self-paced movement during air-off. Neurally, a larger fraction of CA1 cells was active and significantly modulated during air-off. Within the modulated set, singularly tuned cells (time, distance, or speed) predominated over mixed-tuned cells, and speed-modulated cells peaked earlier after stimulus onset or offset than time- or distance-modulated cells. Under Brake, CA1 activity was predominantly singularly tuned to time or movement-in-place, with stronger movement modulation and engagement post-stimulation. Despite substantial single-cell turnover across configurations and phases, population-level analyses revealed a coherent, air-phase-locked organization and distinct movement-related populations across Brake and No-Brake conditions. These results indicate a state-dependent reweighting of sensorimotor features implemented atop a conserved ensemble scaffold in CA1.

neuroscience↗

bioRxiv2022

Generation of a hybrid AppNL-G-F/NL-G-F xThy1-GCaMP6s+/- Alzheimer disease mouse mitigates the behavioral and hippocampal encoding deficits of APP knock-in mutations of AppNL-G-F/NL-G-F mice

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein (App) gene exhibit stereotypical age-dependent amyloid beta (A{beta}) pathology and cognitive impairment without physiologically unrealistic App overexpression. This study investigated the effect of familial AD-linked App mutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity, AppNL-G-F/NL-G-F knock-in (APPki) mice were crossed with Thy1-GCaMP6s+/- (C-TG) mice to generate AppNL-G-F/NL-G-FxThy1-GCaMP6s+/- (A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited A{beta} pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in A{beta} pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect of APP mutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.

neuroscience↗

bioRxiv2022

Hippocampal damage causes retrograde amnesia for objects' visual, but not odour, properties

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67-97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, does not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.

neuroscience↗

bioRxiv2022

Conjunctive and complementary CA1 hippocampal cell populations relate sensory events to immobility and locomotion

This study investigated the dynamics of recruitment of cells in the CA1 region of the hippocampus in response to sensory stimuli presented during immobility, movement, and their transitions. Two-photon calcium imaging of somal activity in CA1 neuron populations was done in head fixed mice. Sensory stimuli, either a light flash or an air stream, were delivered to the mice when at rest, when moving spontaneously, and while they were induced to run a fixed distance on the conveyor belt. Overall, 99% of 2083 identified cells (from 5 mice) were active across one or more of 20 sensorimotor events. A larger proportion of cells were active during locomotion. Nevertheless, for any given sensorimotor event, only about 17% of cells were active. When considering pairs of sensorimotor event types, the active cell population consisted of conjunctive (C [isin] A and B) cells, active across both events, and complementary (C [isin] A not B or C [isin] B not A) cells that were active only during individual events. Whereas conjunctive cells characterised stable representations of repeated sensorimotor events, complementary cells characterised recruitment of new cells for encoding novel sensorimotor events. The moment-to-moment recruitment of conjunctive and complementary cells across changing sensorimotor events signifies the involvement of the hippocampus in functional networks integrating sensory information with ongoing movement. This role of the hippocampus is well suited for movement guidance that secondarily might include spatial behavior, episodic learning and memory, context representation, and scene construction.

neuroscience↗

bioRxiv2019

Effects of social defeat stress and fluoxetine treatment on neurogenesis and behaviour in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behaviour and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress-induced behavioural symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression-like effects, including social avoidance and anxiety-like behaviour. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety-like behaviour. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioural benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

neuroscience↗

bioRxiv2019

Effects of enriched housing on the neuronal morphology of mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

In the central nervous system, certain neurons store zinc within the synaptic vesicles of their axon terminals. This vesicular zinc can then be released in an activity-dependent fashion as an intercellular signal. The functions of vesicular zinc are not entirely understood, but evidence suggests that it is important for some forms of experience-dependent plasticity in the brain. The ability of neurons to store and release vesicular zinc is dependent on expression of the vesicular zinc transporter, ZnT3. Here, we examined the neuronal morphology of mice that lack ZnT3. Brains were collected from mice housed under standard laboratory conditions and from mice housed in enriched environments - large, multilevel enclosures with running wheels, numerous objects and tunnels, and a greater number of cage mates. Golgi-Cox staining was used to visualize neurons for analysis of dendritic length and dendritic spine density. Neurons were analyzed from the barrel cortex, striatum, basolateral amygdala, and hippocampus (CA1). ZnT3 knockout mice, relative to wild type mice, exhibited increased basal dendritic length in the layer 2/3 pyramidal neurons of barrel cortex, independently of housing condition. Environmental enrichment decreased apical dendritic length in these same neurons and increased dendritic spine density on striatal medium spiny neurons. Elimination of ZnT3 did not modulate any of the effects of enrichment. Our results provide no evidence that vesicular zinc is required for the experience-dependent changes that occur in response to environmental enrichment. They are consistent, however, with recent reports suggesting increased cortical volume in ZnT3 knockout mice.

neuroscience↗

bioRxiv2018

Brain-derived neurotrophic factor and TrkB levels in mice that lack vesicular zinc: Effects of age and sex

In certain neurons, zinc ions are stored in synaptic vesicles by zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically to modulate myriad targets. In vitro evidence indicates that these targets may include brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). But the effects of vesicular zinc on BDNF and TrkB in the intact brain are unclear. Studies of mice that lack ZnT3 - and, as a result, vesicular zinc - have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This might be caused by differences in the age or sex of mice tested. In the present study, we measured BDNF and TrkB levels in the hippocampus and neocortex, comparing wild type and ZnT3 knockout mice of both sexes at two ages (5 and 12 weeks). We also examined BDNF mRNA expression and protein levels at an intermediate age (8-10 weeks). We found that, regardless of age or sex, BDNF and TrkB protein levels did not differ between wild type and ZnT3 knockout mice. There were sex-specific differences in BDNF protein and mRNA expression, however. BDNF protein levels increased with age in female mice but not in males. And in females, but not males, ZnT3 KO mice exhibited great hippocampal BDNF mRNA expression than wild type mice. We conclude that, at least in naive mice housed under standard laboratory conditions, elimination of vesicular zinc does not affect BDNF or TrkB protein levels.

neuroscience↗

bioRxiv2018

Elimination of vesicular zinc alters the behavioural and neuroanatomical effects of social defeat stress in mice

Chronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc - zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice.

neuroscience↗