Neuropsychiatric symptoms (NPSs), such as depression and anxiety, are observed in 90% of AD patients and are frequent in those at risk for AD. However, until recently, much of the research narrowly targeted co-morbid depression. Clinical reports have provided evidence that anxiety symptoms predict the conversion to AD, over and beyond the effects of depression, memory loss, and even atrophy. Similarly, epidemiological studies show that neurodegeneration and clinical symptoms occur more rapidly in females once diagnosed. Although most AD studies have been performed using male mice, females represent two-thirds of the AD population and are more susceptible to depression and anxiety. To study how anatomical sex and anxiety impact AD progression, I used our activity-dependent tagging system, the ArcCreERT2 x channelrhodopsin (ChR2)-EYFP x AD (APP/PS1) mice. These mice allow for brain-wide indelible labeling of neurons activated during learning, which then can be compared with secondary neuronal ensembles activated during memory retrieval. The neurons activated at both time points represent a memory trace or engram. Here, we aimed to identify the neural ensembles linking anxiety and memory loss following AD progression by utilizing behavioral studies, calcium imaging and whole-brain microscopy, in female and male mice. We found: 1) Female AD mice exhibited anxiety-like behavior at an earlier age compared to controls and male mice, 2) AD female mice displayed memory deficits as early as 2 months of age, 3) Anxiety-like behavior correlated with memory impairment only in AD female mice, and 4) Unlike their male counterparts, female AD mice showed a decline in memory traces in the CA3 of the hippocampus. We are currently working to translate these findings to humans using the Alzheimer’s disease neuroimaging initiative (ADNI) dataset. We have found that in humans, anxiety predicts transition to dementia and that anxiety has a sex-specific effect on brain atrophy.

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From these initial experiments, we are now examining the ventral hippocampal circuitry underlying neuropsychiatric symptoms in AD and using psychedelics to treat NPSs and cognitive decline.

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In the face of age-related changes, having cognitive reserve (CR) can buffer against neuropathology and cognitive stressors that often lead to degeneration. Brain maintenance, a compliment of CR, refers to the relative absence of change over time with age. Although there are many variables that affect CR, such as age, IQ, socioeconomic status (SES), and stress, higher levels of education are associated with a lower risk of dementia and widely used as an indicator of CR. These findings suggest that improving education can boost CR to act as a defense against dementia and age-related cognitive decline (ARCD). Therefore, it is essential to understand how environmental changes during aging impact CR on a behavioral and neural level. Many studies of CR have been performed using large human datasets, but this hinders our ability to look at brain changes on the cellular level. Longitudinal animal studies provide a great opportunity to gain further insight into the molecular mechanisms of CR’s impact on ARCD. For example, in the Tg2576 Alzheimer’s disease (AD) mouse model, environmental enrichment (EE) did not have long lasting effects on memory capacity as measured by EEG recordings. However, repeated cognitive stimulation using Morris water maze (MWM) training (heretofore considered a proxy for education) regime for 3 months improved memory performance of the 3xTg-AD mouse model. Despite these results, a majority of research has focused on EE alone and less on a more rigorous form of educational training in mice. Therefore, it is essential that we use education or training as a tool to assess CR in mice.

Here, I examine how education affects CR in a novel mouse model. I will use our activity-dependent memory tagging system, the ArcCreERT2 x EYFP mice. These mice allow for brain-wide indelible labeling of neurons activated during learning, which then can be compared with secondary neuronal ensembles activated during memory retrieval. The neurons activated at both time points represent a memory trace or engram. By determining which areas of the brain are involved in maintaining or enhancing CR, we can better understand how to create lifestyle changes or therapeutics.

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Benzodiazepines are anxiolytic drugs that are currently prescribed to patients suffering from anxiety and panic disorders. More specifically, these drugs are often prescribed to combat the anxiety associated with post-traumatic stress disorder (PTSD). However, Benzodiazepines are known to interrupt anterograde memory formation or the formation of new memories. Although benzodiazepines have been in use for over 60 years, the affected brain regions and neuronal mechanisms responsible for this detrimental side-effect are largely unknown. To better understand the long-term memory deficits caused by benzodiazepines, this project aims to analyze neuronal ensemble activation following benzodiazepine injections.

Alzheimer’s disease (AD), a progressive and debilitating neurodegenerative disorder, affects over 6 million people. Of those 6 million people, 2/3rds are women. In fact, the first documented AD patient was a woman, Auguste Deter. Although AD affects women more often than men, a majority of literature probing the etiology of the disease has been male-focused. To obtain a more complete picture of the pathophysiology of AD, it is important to determine the underlying mechanisms that lead to greater female susceptibility. Numerous reports have linked menopause with memory loss, suggesting that the decrease in estrogen and progesterone contributes to dementia transition. Here, we aim to determine how menopause transition periods impact mood, sleep, cognition, and neuronal activity using miniscope technology.

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