Weinshenker Lab

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the beta-amyloid plaques and tau neurofibrillary tangles. A ubiquitous but less recognized feature of AD is the loss of noradrenergic neurons in the LC, and it is now recognized that the LC is among the earliest regions of the brain where pathogenic tau has been detected. We are currently pursuing several different questions to characterize the role of the LC in AD. First, why are LC neurons selectively vulnerable to developing early tau pathology? Second, what are the consequences of early tau pathology on LC function and survival, as well as brain-wide functional connectivity? Third, can tau pathology spread from the LC to interconnected brain regions? Finally, can manipulation of LC activity ameliorate AD-like neuropathology and cognitive deficits in rodent models of the disease? We are using a combination of techniques to answer these questions, including transgenic mice, transgenic rats, viral vectors, behavior, immunohistochemistry, neurochemistry, electrophysiology, and fMRI.

Similar to AD, the LC is among the first regions of the brain to develop PD-like neuropathology, in this case, a-synuclein inclusions, and experiences catastrophic degeneration later in the disease. In fact, many non-motor prodromal PD symptoms (e.g. sleep/wake deficits, mild cognitive impairment, anxiety, depression) have been attributed to LC dysfunction. We recently developed a novel BAC transgenic mouse that expresses human a-synuclein selectively in noradrenergic neurons and showed that these mice recapitulate some aspects of PD-like neuropathology and non-motor symptoms that are consistent with LC hyperactivity. We are continuing to study these animals. We are also testing the hypothesis that the production of neuromelanin, a cytoplasmic pigment that is exclusively produced by catecholaminergic neurons, contributes to LC vulnerability and gene expression changes in early PD.

The mesocorticolimbic DA system has been primarily implicated in the reinforcing effects of drugs of abuse. We know that ventral tegmental area (VTA) dopamine neurons are modulated by input from the LC, but there is evidence that some aspects of this modulation are independent of NE. Our major goal is to determine how the LC co-transmitter galanin and its receptors impact VTA neuron activity and behavioral responses to opioids. Techniques include RNAscope fluorescence in situ hybridization, immunohistochemistry, conditioned place preference, operant iv self-administration, and slice electrophysiology (in collaboration with Carlos Paladini’s lab at UT-San Antonio).

LC activity fluctuates with sleep-wake cycles, and the LC is classically implicated in promoting arousal. However, the circuits underlying the wake-promoting effects of LC activity have not been identified. We are currently using DREADDs, knockout mice that lack NE, and receptor agonists/antagonists to investigate potential interactions between the LC and an understudied population of DA neurons in the ventral periaqueductal gray that may increase arousal.

LC hyperactivity has been implicated in stress responses and anxiety-like behavior, but the neural circuits have not been fully delineated. We are currently studying novelty-induced anxiety-like behavior in knockout mice that lack NE and using c-fos immunohistochemistry, pharmacology, chemogenetics, and genetic capture to identify and control noradrenergic circuits in the forebrain. We are also using conditional knockout mice, transgenic overexpressors, environmental enrichment, and optogenetics to assess the contribution of the LC co-transmitter galanin to stress-induced anxiety-like behavior.