CHARACTERIZATION OF TRANSMEMBRANE PROTEIN 35 EXPRESSION: CONSIDERATIONS OF SEX AND OVARIAN HORMONES

The recently discovered novel neuropeptide transmembrane protein 35 (TMEM35), is believed to modulate chemical signaling within the nervous system. Notably, the TMEM35 protein is detectable in humans, non-human primates and rodents, suggesting a conserved and critical function. Despite this, the functions of TMEM35 are ill-defined in the nervous system and insufficiently studied (currently only three publications). Previous work has identified high expression of TMEM35 in both the ventromedial hypothalamus (VMH) and the limbic circuit of the mouse brain. Due to the known functions of these two regions, this pattern of expression indicates possible roles of this neuropeptide in social behavior and reward processing. Interestingly, TMEM35 mRNA expression exhibits possible sexual dimorphisms in rodents with the overall expression of TMEM35 mRNA being higher in females than in males. However, this qualitative evaluation of sex differences in mRNA expression has not been quantitatively described throughout the brains of male and female rodents. We aimed to anatomically map TMEM35 protein expression in both male and female Syrian hamsters to determine sex differences in expression. Moreover, we hypothesized that ovarian hormones were responsible for the observed sex differences in females. To determine this, we ovariectomized adult female Syrian hamsters to remove the major endogenous source of gonadal steroid hormones, and primed them with estradiol and progesterone to mimic the natural hormonal cycle, or with cottonseed oil vehicle. Tissue was immunohistochemically processed for TMEM35-positive cells. Sex differences in TMEM35 protein expression in which females expressed higher levels than males were found in several brain areas, including in the anterior hypothalamic nucleus (AH), anteroventral periventricular nucleus (AVPV), bed nucleus of the stria terminalis (BNST), dorsomedial hypothalamus (DMH), dorsal lateral septum (LSd), dorsal medial amygdala (MAd), medial caudate (MCU), medial preoptic nucleus (MPN), nucleus accumbens core (NAcc), nucleus accumbens shell (NAcsh), suprachiasmatic nucleus (SCN), and ventromedial hypothalamus (VMH). Of these brain areas, ovarian hormones induced TMEM35 expression in the AH, CA1 of the hippocampal formation, MAd, MCU, NAcsh, PVN, and VMHm. Characterizing how TMEM35 expression is altered as a result of engaging in normal life experiences will give insight into the biology of brain circuitry, and will provide better understanding into how these systems function and could potentially lead to the development of therapeutic treatments to alleviate dysfunctions within each network

Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function

Summary: The effects of repeated stress on cognitive impairment are thought to be mediated, at least in part, by reductions in the stability of dendritic spines in brain regions critical for proper learning and memory, including the hippocampus. Small GTPases are particularly potent regulators of dendritic spine formation, stability, and morphology in hippocampal neurons. Through the use of small GTPase protein profiling in mice, we identify increased levels of synaptic Rap1 in the hippocampal CA3 region in response to escalating, intermittent stress. We then demonstrate that increased Rap1 in the CA3 is sufficient in and of itself to produce stress-relevant dendritic spine and cognitive phenotypes. Further, using super-resolution imaging, we investigate how the pattern of Rap1 trafficking to synapses likely underlies its effects on the stability of select dendritic spine subtypes. These findings illuminate the involvement of aberrant Rap1 regulation in the hippocampus in contributing to the psychobiological effects of stress

A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring.

Mounting epidemiologic and scientific evidence indicates that many psychiatric disorders originate from a complex interplay between genetics and early life experiences, particularly in the womb. Despite decades of research, our understanding of the precise prenatal and perinatal experiences that increase susceptibility to neurodevelopmental disorders remains incomplete. Sleep apnea (SA) is increasingly common during pregnancy and is characterized by recurrent partial or complete cessations in breathing during sleep. SA causes pathological drops in blood oxygen levels (intermittent hypoxia, IH), often hundreds of times each night. Although SA is known to cause adverse pregnancy and neonatal outcomes, the long-term consequences of maternal SA during pregnancy on brain-based behavioral outcomes and associated neuronal functioning in the offspring remain unknown. We developed a rat model of maternal SA during pregnancy by exposing dams to IH, a hallmark feature of SA, during gestational days 10 to 21 and investigated the consequences on the offspring's forebrain synaptic structure, synaptic function, and behavioral phenotypes across multiples stages of development. Our findings represent a rare example of prenatal factors causing sexually dimorphic behavioral phenotypes associated with excessive (rather than reduced) synapse numbers and implicate hyperactivity of the mammalian target of rapamycin (mTOR) pathway in contributing to the behavioral aberrations. These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment