The ability to form aversive memories (e.g., connecting stimuli in the environment with the negative events they predict) is crucial to survival and is well-conserved across species. Alterations in this system, however, can lead to maladaptive or inappropriate fear responding outside of situations in which a fear response is warranted. This ?generalized? fear response, in which fearful behavior is expressed outside of the context or environment in which it was acquired, is a hallmark symptom of several human neuropsychiatric disorders like post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The inability to appropriately use context to guide fear responding is a common process that, when treated, could target symptomology underlying several disorders, most of which cause significant distress to the afflicted. Most research on the encoding and retrieval of contextual processing in fear memory has focused on subcortical regions like the hippocampus and the amygdala. Recent data has begun to suggest a critical role for the retrosplenial cortex (RSC) in the acquisition and expression of these memories. Previous work has primarily used spatially and temporally imprecise manipulations of the RSC, making it difficult to understand the exact role of this relatively large structure in encoding and retrieval of both the event-related (i.e., ?what?) and context-related (i.e., ?where?) aspects of aversive memory. The overarching hypothesis of this proposal is that the anterior region of the RSC (i.e., the aRSC) is important for encoding of the event-related aspects of memory (the ?what? memory) and that the posterior region (i.e., the pRSC) independently and dissociably encodes the context-related information (that ?where? memory).
In Specific Aim 1, we will examine differential contributions of aRSC and pRSC to the to the independent formation of event-related and contextual memory, and their subsequent association, via a modified form of contextual fear conditioning.
In Specific Aim 2, we will examine the contributions of both regions to the retrieval of event-related and contextual memory, using both contextual fear conditioning and trace fear conditioning (a type of cued fear conditioning that is crucially dependent on the RSC). In all studies, neurons in either aRSC or pRSC will be optogenetically silenced, a technique that allows for unprecedented spatial and temporal precision. This temporary and reversible inactivation will allow for examination of the type of information processed within the RSC, as well as for the discrete roles of the RSC during aversive event-related and contextual memory formation. By investigating the neural substrates that support these forms of learning, this work could identify a new target in treating disorders in which the learning controlled by the RSC is likely dysregulated.
Pavlovian fear conditioning (in which neutral stimuli come to predict negative events) in rodents has become the gold standard for studying aversive memory formation in the laboratory and the context (or environment) in which this learning takes can influence how these memories are both acquired and expressed at a later time. The proposed project aims to identify the neural and molecular mechanisms that underlie learning about the context during Pavlovian fear conditioning, as abnormalities in contextual processing can lead to inappropriate (or ?generalized?) responding to aversive stimuli in safe or neutral environments. By studying both the basic behavior and function of the related brain structures (e.g., the retrosplenial cortex) in normally-behaving animals, these studies could inform more targeted therapeutic interventions.
