Biology subjects

Moy, S.

Publications and source records attributed to Moy, S..

4 recordsLinked to original sources

bioRxiv2024

Microglia promote neurodegeneration and hyperkatifeia during withdrawal and prolonged abstinence from chronic binge alcohol

Proinflammatory microglial polarization, neuronal death, and hyperkatifeia/negative affect during withdrawal are key features of alcohol use disorder (AUD). However, the role microglia play in the development of AUD-related neuronal and behavioral pathology is unclear. Given the ability of microglia to regulate neuronal function, it was hypothesized that proinflammatory microglia promote neuronal death and hyperkatifeia during prolonged abstinence from binge alcohol. Proinflammatory signaling and affective state were assessed in mice either during acute withdrawal (24h) or abstinence (>4 weeks) to binge alcohol exposure. Ten days of binge alcohol increased proinflammatory gene signaling 24h after EtOH, which lasted weeks into withdrawal. Alcohol reduced brain-derived neurotrophic factor (BDNF) in hyperkatifeia-associated regions (i.e., the central amygdala and infralimbic cortex) during acute withdrawal and caused persistent microglial structural changes and loss of microglial BDNF in the BNST during abstinence. This was associated with increased anxiety-like behavior and hyperarousal, with persistent enhancement of conditioned fear memory during abstinence. Inhibition of proinflammatory microglia with Gi designer receptors exclusively activated by designer drugs (DREADDs) blocked neuronal death and prevented persistent proinflammatory gene induction and hyperkatifeia in female mice. Thus, this identifies a direct role for microglia in the development of AUD-related neuropathology and behavioral dysfunction, implicating microglia as cellular targets for the prevention of AUD phenotypes.

neuroscience↗

bioRxiv2023

CTCF is essential for proper mitotic spindle structure and anaphase segregation

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus.

cell biology↗

bioRxiv2020

Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

The peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1) is known as a transcriptional co-activator in peripheral tissues but its function in the brain remains poorly understood. Various brain-specific Pgc1 isoforms have been reported in mice and humans, including transcripts derived from a novel promoter about [~]580 Kb upstream from the reference gene. These isoforms incorporate repetitive sequences from the simple sequence repeat (SSR) and short interspersed nuclear element (SINE) classes and are predicted to give rise to proteins with distinct amino-termini. In this study, we show that a SINE-containing isoform is the predominant form of Pgc1 expressed in neurons. We then generated a mouse carrying a mutation within the SINE to study its functional role in the brain. By combining genomics, biochemical and behavioural approaches, we show that this mutation leads to impaired motor coordination in females, but not male mice, associated with the upregulation of hundreds of cerebellar genes. Moreover, our analysis suggests that known nuclear receptors interact with this isoform of PGC1 in the brain to carry out the female transcriptional program. These data expand our knowledge on the role of Pgc1 in the brain and help explain its conflicting roles in neurological disease and behavioural outcomes.

neuroscience↗

bioRxiv2017

CA2 Neuronal Activity Controls Hippocampal Oscillations and Social Behavior

Hippocampal oscillations arise from coordinated activity among distinct populations of neurons and are associated with cognitive functions and behaviors. Although much progress has been made toward identifying the relative contribution of specific neuronal populations in hippocampal oscillations, far less is known about the role of hippocampal area CA2, which is thought to support social aspects of episodic memory. Furthermore, the little existing evidence on the role of CA2 in oscillations has led to conflicting conclusions. Therefore, we sought to identify the specific contribution of CA2 pyramidal neurons to brain oscillations using a controlled experimental system. We used excitatory and inhibitory DREADDs in transgenic mice to acutely and reversibly manipulate CA2 pyramidal cell activity. Here, we report on the role of CA2 in hippocampal-prefrontal cortical network oscillations and social behavior. We found that excitation or inhibition of CA2 pyramidal cells bidirectionally regulated hippocampal and prefrontal cortical low gamma oscillations and inversely modulated hippocampal ripple oscillations. Further, CA2 inhibition impaired social approach behavior. These findings support a role for CA2 in low gamma generation and ripple modulation within the hippocampus and underscore the importance of CA2 neuronal activity in extrahippocampal oscillations and social behavior.

neuroscience↗