We have shown that the same brain regions and circuits vulnerable to aging are responsive to circulating estrogen levels, suggesting that critical interactions between reproductive senescence and brain aging may affect excitatory synaptic transmission and cognitive performance. In fact, estrogen treatment in aged female monkeys protected the vulnerable class of synapses and restored cognitive performance to that of young monkeys. Importantly, the effects of estrogen on these neurons show that certain age-associated synaptic alterations may be reversible, leading to the protection of cognitive performance observed in these monkeys. These effects of estrogen give us a molecular and therapeutic entry point to explore additional interventions and strategies to protect against synaptic aging. If we can prevent the synaptic aging of these circuits while still largely intact, we may be able to protect individuals against the earliest stages of cognitive decline and in turn, prevent the transition to the death of these circuits that underlies AD.
A parallel area of research in our lab investigates the effects of behavioral stress on neurons in the prefrontal cortex. We have shown that stress leads to dendritic retraction on pyramidal neurons in prefrontal cortex, and this leads to cognitive decline. Importantly, if stress is discontinued these neurons recover, both structurally and functionally. In addition, the specific neuronal responses to stress differ between males and females. All of these studies were done in young animals, but recently, we were able to link our investigations into neuronal aging with our interest in behaviorally (i.e., stress)- induced plasticity. While the dendrites of prefrontal neurons in young animals recover from stress-induced retraction, this capacity for recovery is absent in middle-aged and aged animals. Furthermore, prefrontal neurons in middle-aged and aged rats lose spines with aging in the absence of stress and are further stress-induced synaptic loss or plasticity. We are now pursuing the mechanisms responsible for age-related loss of experience dependent plasticity.
PhD, Johns Hopkins University