An Exploration into the Non-Photic Influence of Acetylcholinesterase Inhibitors on Circadian Rhythms

While light is the dominant zeitgeber (“time giver”) for the circadian system, nonphotic cues, such as exercise and arousal, also affect circadian rhythmicity. Our lab has reported that cholinergic innervation of the suprachiasmatic nucleus arising from the basal forebrain is both necessary and sufficient for phase shifting circadian rhythms in a nonphotic manner. Therefore, the present study investigated a new avenue for modulating cholinergic activity in a less invasive manner by testing whether enhancing acetylcholine neurotransmission with acetylcholinesterase (AChE) inhibitors will cause nonphotic-like phase shifts of the circadian system. Three different AChE inhibitors were explored (Donepezil, Rivastigmine, and Tacrine) at varying doses. First, Syrian hamsters were housed in constant darkness (DD), and were administered an intraperitoneal (IP) injection of one of the AChE inhibitors or vehicle control in counterbalanced order six hours before their activity onset, a phase when nonphotic treatments elicit phase advances. The second hypothesis was that nonphotic phase shifts elicited by AChE inhibitor administration requires acetylcholine activity at the SCN. Hamsters were given a microinjection of either saline or the acetylcholine antagonist Atropine to the SCN 10 minutes prior to a CT6 injection of donepezil (10mg/kg). In experiment one, Donepezil at 10mg/kg had the most robust phase advances relative to the controls. In experiment two, the results were mixed with no significant differences were found between conditions, including the baseline measurement of Donepezil/control

Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

Summary: The hypothalamus plays a crucial role in the modulation of social behavior by encoding internal states. The hypothalamic hypocretin/orexin neurons, initially identified as regulators of sleep and appetite, are important for emotional and motivated behaviors. However, their role in social behavior remains unclear. Using fiber photometry and behavioral analysis, we show here that hypocretin neurons differentially encode social discrimination based on the nature of social encounters. The optogenetic inhibition of hypocretin neuron activity or blocking of hcrt-1 receptors reduces the amount of time mice are engaged in social interaction in males but not in females. Reduced hcrt-1 receptor signaling during social interaction is associated with altered activity in the insular cortex and ventral tegmental area in males. Our data implicating hypocretin neurons as sexually dimorphic regulators within social networks have significant implications for the treatment of neuropsychiatric diseases with social dysfunction, particularly considering varying prevalence among sexes

Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons

Alzheimer’s disease (AD) is a progressive degenerative disorder that results in a severe loss of brain cells and irreversible cognitive decline. Memory problems are the most recognized symptoms of AD. However, approximately 90% of patients diagnosed with AD suffer from behavioral symptoms, including mood changes and social impairment years before cognitive dysfunction. Recent evidence indicates that the dorsal raphe nucleus (DRN) is among the initial regions that show tau pathology, which is a hallmark feature of AD. The DRN harbors serotonin (5-HT) neurons, which are critically involved in mood, social, and cognitive regulation. Serotonergic impairment early in the disease process may contribute to behavioral symptoms in AD. However, the mechanisms underlying vulnerability and contribution of the 5-HT system to AD progression remain unknown. Here, we performed behavioral and electrophysiological characterizations in mice expressing a phosphorylation-prone form of human tau (hTauP301L) in 5-HT neurons. We found that pathological tau expression in 5-HT neurons induces anxiety-like behavior and alterations in stress-coping strategies in female and male mice. Female mice also exhibited social disinhibition and mild cognitive impairment in response to 5-HT neuron-specific hTauP301L expression. Behavioral alterations were accompanied by disrupted 5-HT neuron physiology in female and male hTauP301L expressing mice with exacerbated excitability disruption in females only. These data provide mechanistic insights into the brain systems and symptoms impaired early in AD progression, which is critical for disease intervention