This project is concerned with understanding mechanisms of context-associated fear (CFC) and fear extinction (CFE) memory consolidation during REM sleep. Memory consolidation is a process whereby a recent experience transforms into stable, long-term memories. A large number of studies in both animals and humans have shown that REM sleep and REM sleep-associated physiological signs facilitate consolidation of many different categories of memories, including emotional memory. Deficits in emotional memory consolidation have been associated with impaired regulation of REM sleep signs in a number of neuro-psychiatric disorders, including Alzheimer's disease and anxiety disorders. Despite the major impact of REM sleep-associated physiological signs on memory consolidation, remarkably little is known about the cellular, molecular and/or network mechanisms underlying REM sleep-associated emotional memory processing. Recent work in the PI's lab has focused on a prominent physiological sign of REM sleep - phasic pontine-wave (P-wave) - that is ideally suited to promote memory consolidation and neuronal plasticity during REM sleep. The central hypotheses are that after training: 1) excitation of the phasic P-wave generator (SubCD) during REM sleep is critical for the consolidation of memory, and 2) activation of the P-wave generator requires activating inputs from the PPT cholinergic cells to the SubCD.
Three specific aims have been designed to systematically test these hypotheses: 1. Identify the mechanism responsible for the activation of the P-wave generator following CFC and CFE training. 2. Determine if the activation of the P-wave generator is sufficient for REM sleep- associated consolidation of CFC and CFE memory. Additional experiments will determine whether inactivation of the P-wave generator impairs memory consolidation, even in the presence of sufficient REM sleep. 3. Determine that the activation of the P-wave generator is a causal factor for CFC memory consolidation through amygdala-hippocampal theta synchronization and BDNF and Arc gene expressions in the dorsal hippocampus (DH). The experiments will involve adult male and female rats as subjects. Context-associated fear and fear extinction learning in the rats have proven to be an excellent model to study mechanisms of emotional memory in human. Molecular techniques will be used to block localized BDNF synthesis and neuronal activity, and dual viral DREADD as well as excitatory and inhibitory DREADDs will be used to manipulate activities of P-wave generating neuronal network and P-wave activity. Recordings of neck muscle EMG and EEG activities from frontal cortex, hippocampus, and pons will be used to identify sleep-wake stages. Local field potentials (LFP) will be recorded from the DH, amygdala, medial prefrontal cortex, and pons to analyze amygdala-hippocampal theta wave synchronization. We believe that the results of these studies will extend the leading edge of knowledge on the basic neurobiological mechanisms of sleep-dependent emotional memory processing, which will facilitate vital advancement in the areas of cognitive neuroscience and sleep functionality.
Deficits in memory consolidation are associated with a number of neurological, psychiatric, as well as age- related disorders, which collectively affect large segments of our population. This research is devoted to understanding the REM sleep-associated cellular, molecular, and network mechanisms that are involved in memory consolidation. Since little to nothing is presently known about the cellular, molecular, and network mechanisms that regulate memory consolidation, the results of this proposed work have the potential to pioneer the development of novel therapeutic approaches for memory consolidation-associated cognitive deficits seen in a number neuropsychiatric disorders (Alzheimer's, Huntington's, Parkinson's, Anxiety disorders, Depression, Schizophrenia, Stroke, and Addiction) and in the growing aging population.
| Dulka, Brooke N; Koul-Tiwari, Richa; Grizzell, J Alex et al. (2018) Dominance relationships in Syrian hamsters modulate neuroendocrine and behavioral responses to social stress. Stress :1-6 |
