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1	Activity patterns of central amygdala neurons in a mouse model of narcolepsy Begovic, Jelena 11 June 2019 (has links) Narcolepsy is a disorder of unstable wake and sleep states caused by the lack of orexin neurons which degenerate most likely as a consequence of an autoimmune process. The state instability of narcolepsy includes rapid eye movement (REM) sleep intruding into wake in the form of dream-like hallucinations and cataplexy, muscle paralysis (atonia) much like occurs in REM sleep. In mice lacking orexin peptides, cataplexy is also observed with similar presentation as in humans of muscle paralysis during wakefulness which is often triggered by positive emotions. Prior research showed that the activation of the central amygdala is sufficient to promote cataplexy in a mouse model of narcolepsy. The central amygdala (CeA) contains a variety of neuronal types, and we hypothesize that γ-aminobutyric acid (GABA)-ergic neurons expressing the oxytocin receptor (OTR) mediate cataplexy as these neurons project to a known REM sleep atonia-regulating region, the ventrolateral periaqueductal gray (vlPAG)/lateral pontine tegmentum (LPT), and, as oxytocin (OT) sensitive neurons in the amygdala, likely participate in emotional processing and social behavior. In this study, we used fiber photometry to investigate the behavior of these neurons in response to social and rewarding stimuli, during emotion-triggered cataplexy, and across arousal states in an effort to define their potential role in emotion-triggered cataplexy. Initial recordings were conducted at too low an excitation light power to stimulate the green fluorescent calcium indicator, GCaMP6s, but were useful in optimizing MATLAB analysis and behavioral tests later done at higher LED power. The second series of recordings with higher excitation light power and better signal to noise ratio, showed increased activity in response to social interaction and reward, prior to REM transitions, and decreased activity during cataplexy confirming patterns seen in initial recordings. In recordings with higher excitation light, these responses appear to occur before interaction with stimulus mice or reward stimulus. In the future, additional recordings with a higher signal to noise ratio will be needed to confirm these results. In conclusion, responses of CeA-OTR neurons to social and rewarding stimuli, cataplexy, and at REM transitions are in support of a possible role of these neurons in emotion-triggered cataplexy which can be tested using additional methods, such as optogenetics. Neurosciences Activity Cataplexy Emotion Fiber photometry Narcolepsy
2	Characterizing Effects of Sphingosine-1-Phosphate Receptor 1 Activation in Subtypes of Central Amygdala Neurons and Effects of Prenatal Methadone Exposure on Motor Cortex Neurons in Mice Mork, Briana E. 04 1900 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. S1P receptor (S1PR) ligands have been utilized as an effective immunosuppressant, treatment in multiple sclerosis and studied as a treatment for pain. The primary cellular response to S1P is thought to be elicited through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1 signaling affects neuronal excitability in the central amygdala (CeA), a supraspinal node of the descending pain pathway. The CeA is made up of a heterogenous population of neurons which form complex local and long-range circuits. The central lateral amygdala (CeL) consists of two major populations of inhibitory neurons identified by expression of the peptides somatostatin (Sst) and protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control over local circuits within the CeL and play a critical role in pain modulation. I utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL neurons for whole-cell electrophysiology in acute brain slice. This strategy allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal pain pathways. My second goal was to assess the physiology of motor cortex neurons in mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist used for opioid maintenance therapy and chronic pain management. Methadone treatment for opioid use disorder in pregnant women can result in structural changes within the brain of their offspring causing and developmental delays to their children, including poorer motor performance. Using a mouse model of prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses of cellular morphology, I elucidated the effects of PME on primary motor cortex (M1) output layer 5 (L5) neurons, which encompass the major cortical output pathway for motor control. My findings provide the first evidence that PME disrupts neuronal firing, subthreshold properties, and strength of local inputs onto M1 L5 neurons in prepubescent mice. / 2023-05-05 Central Amygdala Electrophysiology Methadone Motor Cortex Neurons Spingosine-1-Phosphate Receptor 1
3	Female-Specific Role of Ciliary Neurotrophic Factor in the Medial Amygdala in Promoting Stress Responses Jia, Cuihong, Gill, Wesley D., Lovins, Chiharu, Brown, Russell W., Hagg, Theo 01 March 2022 (has links) Ciliary neurotrophic factor (CNTF) is produced by astrocytes which have been implicated in regulating stress responses. We found that CNTF in the medial amygdala (MeA) promotes despair or passive coping, i.e., immobility in an acute forced swim stress, in female mice, while having no effect in males. Neutralizing CNTF antibody injected into the MeA of wildtype females reduced activation of downstream STAT3 (Y705) 24 and 48 h later. In concert, the antibody reduced immobility in the swim test in females and only after MeA injection, but not when injected in the central or basolateral amygdala. Antibody injected into the male MeA did not affect immobility. These data reveal a unique role of CNTF in female MeA in promoting despair or passive coping behavior. Moreover, 4 weeks of chronic unpredictable stress (CUS) increased immobility in the swim test and reduced sucrose preference in wildtype CNTF+/+, but not CNTF-/- littermate, females. Following CUS, 10 min of restraint stress increased plasma corticosterone levels only in CNTF+/+ females. In males, the CUS effects were present in both genotypes. Further, CUS increased CNTF expression in the MeA of female, but not male, mice. CUS did not alter CNTF in the female hippocampus, hypothalamus and bed nucleus of stria terminalis. This suggests that MeA CNTF has a female-specific role in promoting CUS-induced despair or passive coping, behavioral anhedonia and neuroendocrine responses. Compared to CNTF+/+ mice, CNTF-/- mice did not show differences in CUS-induced anxiety-like behavior and sensorimotor gating function as measured by elevated T-Maze, open field and pre-pulse inhibition of the acoustic startle response. Together, this study reveals a novel CNTF-mediated female-specific mechanism in stress responses and points to opportunities for developing treatments for stress-related disorders in women. anhedonia BLA basolateral amygdala BNST bed nucleus of stria terminalis CNTF ciliary neurotrophic factor CRF corticotropin releasing factor CUS chronic unpredictable stress CeA central amygdala Chronic unpredictable stress HPA hypothalamic-pituitary-adrenal Hyp hypothalamus IL-6 interleukin-6 LIF leukemia inhibitory factor MeA medial amygdala neuroendocrine response Neutralizing antibody PAG periaqueductal grey PTSD post-traumatic stress disorder PVN paraventricular nucleus passive stress-coping stereotaxic injection TNF tumor necrosis factor mPFC medial prefrontal cortex Biomedical Sciences

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