Biology subjects

Cham, H.

Publications and source records attributed to Cham, H..

4 recordsLinked to original sources

bioRxiv2024

Postmortem tissue biomarkers of menopausal transition

The menopausal transition (MT) is associated with an increased risk for many disorders including neurological and mental disorders. Brain imaging studies in living humans show changes in brain metabolism and structure that may contribute to the MT-associated brain disease risk. Although deficits in ovarian hormones have been implicated, cellular and molecular studies of the brain undergoing MT are currently lacking, mostly due to a difficulty in studying MT in postmortem human brain. To enable this research, we explored 39 candidate biomarkers for menopausal status in 42 pre-, peri-, and post-menopausal subjects across three postmortem tissues: blood, the hypothalamus, and pituitary gland. We identified thirteen significant and seven strongest menopausal biomarkers across the three tissues. Using these biomarkers, we generated multi-tissue and tissue-specific composite measures that allow the postmortem identification of the menopausal status across different age ranges, including the "perimenopausal", 45-55-year-old group. Our findings enable the study of cellular and molecular mechanisms underlying increased neuropsychiatric risk during the MT, opening the path for hormone status-informed, precision medicine approach in womens mental health.

neuroscience↗

bioRxiv2023

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here we reveal molecular substrates in the key reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine in mice. We find shared involvement of X chromosome and estrogen signaling gene regulation in enhanced conditioning responses seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to acute cocaine exposure by increasing the accessibility of neuronal chromatin enriched for the binding sites of {Delta}FosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential closing of neuronal chromatin, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, exposure to early-life stress, and absence of the second X chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to understand sex-specific neuronal mechanisms underlying cocaine use disorder.

neuroscience↗

bioRxiv2019

Multiplexed code of navigation variables in the anterior limbic system

The brains navigation system integrates multimodal cues to create a sense of position and orientation. Here we used a multimodal model to systematically assess how neurons in the anterior thalamic nuclei, retrosplenial cortex and anterior hippocampus of mice, as well as in the cingulum fiber bundle and the white matter regions surrounding the hippocampus, encode an array of navigational variables when animals forage in a circular arena. In addition to coding head direction, we found that some thalamic cells encode the animals allocentric position, similar to place cells. We also found that a large fraction of retrosplenial neurons, as well as some hippocampal neurons, encode the egocentric position of the arenas boundary. We compared the multimodal model to traditional methods of head direction tuning and place field analysis, and found that the latter were inapplicable to multimodal regions such as the anterior thalamus and retrosplenial cortex. Our results draw a new picture of the signals carried and outputted by the anterior thalamus and retrosplenial cortex, offer new insights on navigational variables represented in the hippocampus and its vicinity, and emphasize the importance of using multimodal models to investigate neural coding throughout the navigation system.

neuroscience↗

bioRxiv2019

Sex and Estrous Cycle Effects on Anxiety- and Depression-related Phenotypes in Two-hit Developmental Stress Model

Stress during sensitive developmental periods can adversely affect physical and psychological development and contribute to later-life mental disorders. In particular, adverse experiences during childhood dramatically increase the risk for the development of depression and anxiety disorders. Although women of reproductive age are twice as likely to develop anxiety and depression than men of the corresponding age, little is known about sex-specific factors that promote or protect against the development of psychopathology. To examine potential developmental mechanisms driving sex disparity in risk for anxiety and depression, we established a two-hit developmental stress model including maternal separation in early life followed by social isolation in adolescence. Our study shows complex interactions between early-life and adolescent stress, between stress and sex, and between stress and female estrogen status in shaping behavioral phenotypes of adult animals. In general, increased locomotor activity and body weight reduction were the only two phenotypes where two stressors showed synergistic activity. In terms of anxiety- and depression-related phenotypes, single exposure to early-life stress had the most significant impact and was female-specific. We show that early-life stress disrupts the protective role of estrogen in females, and promotes female vulnerability to anxiety- and depression-related phenotypes associated with the low-estrogenic state. We found plausible transcriptional and epigenetic alterations in psychiatric risk genes, Nr3c1 and Cacna1c, that likely contributed to the stress-induced behavioral effects. In addition, two general transcriptional regulators, Egr1 and Dnmt1, were found to be dysregulated in maternally-separated females and in animals exposed to both stressors, respectively, providing insights into possible transcriptional mechanisms that underlie behavioral phenotypes. Our findings provide a novel insight into developmental risk factors and biological mechanisms driving sex differences in depression and anxiety disorders, facilitating the search for more effective, sex-specific treatments for these disorders.

neuroscience↗