Although fear responses facilitate self-preservation by increasing vigilance and helping an animal avoid potential danger, the inability to regulate fear responses can be maladaptive when it prevents the animal from engaging in other goal-directed activities. Our lab is interested in the circuit-based mechanism by which safety signals gate the expression of either fear or safety-related behaviors. Safety signals are stimuli that predict the explicit absence of an aversive outcome and can modulate fear responding through a process known as conditioned inhibition.

We combine in-vivo calcium imaging (fiber photometry) with chemogenetic (DREADDs) and optogenetic techniques to analyze the role of the neural circuits linked to emotional behaviors as well as their pathology in safety learning.

Our previous work has identified ventral hippocampal neurosn projectinv to the prelimbic prefrontal cortex (VH-PL) as one node in the circuitry mediating fear inhibition, conserved across humans and mice (Meyer et al., 2019, PNAS). Extending this, we use Cre-dependent fluorescent calcium indicators (AAV-FLEX-GCaMP6) to establish the relative activity of ventral hippocampal neurons projecting to regions key to fear processing, including the amygdala and prefrontal cortex, during the acquisition of safety learning as well as the inhibition of fear on both short- and long-term scales.

The mechanism by which PL integrates information from VH and further distributes this information in service of fear inhibition remains to be determined. VH innervates both excitatory pyramidal neurons and inhibitory local interneurons in PL, with the functional activation of the two neuron types depending on previous experience with fear or safety cues as well as the relative level of threat or safety in the current environment. We use a spectrally resolved (i.e., two-color) fiber photometry system to record simultaneously from VH projections and distinct populations of prefrontal principal neurons and interneurons to determine the functional targets of VH neurons and their relative activity under varying conditions of threat and safety.

We examine patterns of neural activity during safety signal training as well as subsequent tests of fear inhibition in order to establish a neural profile for fear and safety behavior and a metric of how this profile changes over time as a mouse learns.

Evidence in both humans and animals has indicated that adolescents are sensitive to threat, and that fear is easily generalized and retained during this developmental stage. Adolescents have been shown to exhibit increased acquisition of cued fear as well as diminished extinction learning relative to both younger and older individuals. Moreover, anxiety disorders are highly prevalent in developing populations, with diagnoses peaking during adolescence. Unfortunately, conventional behavioral treatments such as cognitive behavioral therapy are ineffective for a notable percentage of the adolescent population. Previously, mitigating elevations in fear responding during adolescence has only been possible through increased exposure to extinction protocols, or pharmacological intervention.

Our research investigates the possibility that safety signal learning may provide a unique avenue to address this issue (e.g., Meyer et al., 2021). Our research aims to elucidate the mechanism by which safety signals gate the expression of fear and safety-related learning during development, and how this may translate to processes of fear regulation.

The role of interneurons in maintaining the balance between excitation and inhibition in the prefrontal cortex is well known. This balance facilitates both the efficiency and appropriateness of a behavior in response to the surrounding environment. Work in Meyer lab tests for a causal link between prefrontal interneuron activity and the inhibition of fear during adolescence.

We examine distinct subpopulations of interneurons (e.g., PV and SST), thus providing an important and completely unique contribution to the identification of circuit mechanisms underlying affective learning and behavior.

We employ a “targeted recombination in active populations” (TRAP) viral system for tagging Fos-activated neurons, combined with either halorhodopsin (NpHR)-mediated inhibition or channelrhodopsin-2 (ChR2)-mediated activation techniques. This allows us to evaluate the extent to which activity in ensembles of prefrontal interneurons with a functional role in fear inhibition (i.e., "safety engrams") is necessary for safety learning or sufficient to inhibit fear, even in the absence of a safety signal. In line with evidence from mice that safety signals can be used as a behavioral intervention to attenuate depression-like behaviors, this research emphasizes the potential for safety signals to facilitate traditional methods of fear regulation (e.g., extinction) and reduce anxiety-like behaviors.

The role of interneurons in maintaining the balance between excitation and inhibition in the prefrontal cortex is well known. This balance facilitates both the efficiency and appropriateness of a behavior in response to the surrounding environment. During adolescence, the emergence and dynamic functional remodeling of the prefrontal interneuron system can shift the balance of excitation and inhibition. Yet, the implications of this remodeling for cognitive development and the capacity for emotional and behavioral regulation are unknown. Maturation within prefrontal inhibitory microcircuitry can alter the synaptic strength of inputs to, as well as projections from the prefrontal cortex, in turn altering prefrontal function. Thus, it is likely that inhibitory microcircuit development is a key mechanistic component mediating differences in behavioral regulation during adolescence.

Research in Meyer Lab aims to systematically profile inhibitory microcircuit development in prefrontal cortex (PL, IL, OFC) using immunohistochemical and calcium imaging techniques. Work in this area will provide a link between microcircuit development and the environmental responsiveness of microcircuit components.

An additional question of great interest to our lab is how the environment and individual experiences impact the functional integration of neurons in the prefrontal cortex as well as both risk and resiliency for psychiatric disease. To this end, work in our lab will investigate how exposure to negative (e.g., stress) and positive (e.g., learned safety, environmental enrichment) experiences shape the trajectory of brain development and impact behavior across the lifespan.

What should we know about the services you provide? Better descriptions result in more sales.