We are interested in understanding how oscillatory activity, both neuronal (i.e. brain rhythms) and physiological (e.g. circadian rhythms), relates to limbic networks underlying fear learning, depression and anxiety. We therefore run a number of projects in parallel, all ultimately contributing to our understanding of how periodic orbits, whether reflecting coordinated activity patterns between different types of neuron or endogenously generated biochemical cycles, alter fear processing in the brain and the resulting fear response.
We also focus in sensory stimuli, whether in basic or complex forms, that contribute to our biological rhythms. We therefore carry out behavioral studies for understanding the effects of various environmental inputs, ranging from periodic light pulses to cycles of social activity, in the aforementioned cognito-affective processes.
Basal Forebrain Modulation of Acute and Chronic Fear
The medial septal nucleus of basal forebrain is required for the emergence of hippocampal theta oscillation as well as hippocampal-dependent learning and memory, such as trace eye-blink conditioning and spatial navigation. Septo-hippocampal projections therefore play a significant role in modulating local network computations of this limbic structure. Utilizing selective neuronal inactivation techniques and a variety of behavioral tasks, we are testing whether a similar basal forebrain modulatory mechanism holds true for the amygdala and the bed nucleus of the stria terminalis (BNST); two closely-related group of nuclei, orchestrating large-scale neuronal networks respectively underlying depression and anxiety. We postulate that, as septo-hippocampal projections are required for hippocampal network oscillations and hippocampal forms of learning, similar modulatory basal forebrain projections to other limbic structures underlie learning processes run by those structures by contributing to local oscillations. As such, basal forebrain innervation of the basolateral amygdala must have a key role in fear learning and acute fear response, while a potential basal forebrain projection to the BNST is required for sustained fear.
Basal Forebrain Afferents to the Amygdala and the BNST
The basal forebrain nuclei send cholinergic, glutamatergic, GABAergic and peptidergic projections to several limbic structures underlying diverse forms of memory and affective processes. Combining tract-tracing and immunohistochemistry, we are investigating specific basal forebrain neuronal groups innervating different subnuclei of the amygdala and the BNST. We aim to test the specific function of these particular basal forebrain-limbic system projections in several behavioral paradigms by using chemogenetics (i.e. utilizing Designer Receptors Exclusively Activated by Designer Drugs - DREADDs).
Ameliorative Effects of Light on Behavioral Despair/Depression
Bright light therapy, also known as phototherapy, is used to treat different types of depression, especially major depressive disorder with seasonal pattern (i.e. seasonal affective disorder). In line with this growing body of research and clinical applications, our laboratory showed that a single 12-hour exposure to light during the dark phase of a 12h Light - 12h Dark cycle has a substantial ameliorative effect on behavioral despair in rats. Ongoing research aims to discover the parameters of photic stimulation that will optimize the antidepressant effect of light.
The Effects of Environmental Enrichment on Mood and Cognition
Rodent models of environmental enrichment are well-known to increase performance in hippocampal forms of learning. However, the behavioral effects of this paradigm is not clear concerning animal models of depression (e.g. behavioral despair). Some studies report ameliorative/antidepressant effects, while others point to an increase in depressive behavior in the Forced Swim Test (FST). Starting from this discrepancy in the literature, we aim to evaluate and categorize the differential effects of environmental enrichment in a number of cognitive and affective paradigms, and identify the underlying limbic circuits.
Social Buffering of Acute Stress Response
Social bonding decreases psychological (di)stress levels, whether it is acute or chronic (i.e. anxiety). This positive impact is known as social buffering. Stress has versatile physiological and behavioral effects; whose underlying neuronal correlates are difficult to decipher under naturalistic designs. Utilizing a controlled environmental setup with rats, we examine the ameliorative effects of social buffering following acute restraint stress. We hypothesize that company of a conspecific (vs. being alone) leads to higher exploratory and risk-taking behavior as measured in the Multivariate Concentric Square Field, but no change in anxiety levels assessed by the Elevated Plus Maze. We combine ultrasonic vocalization recordings, behavioral testing and immunohistochemistry for the immediate early gene protein c-Fos, to pinpoint some of the limbic correlates of social buffering.
Antidepressant Effects of Ketamine
It was published by our laboratory that a single anesthetic dose of ketamine, a dissociative non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has a prolonged ameliorative effect on behavioral despair, a rodent model of depression. With a growing body of clinical trials, this anesthetic substance now emerges as a proper antidepressant. We are currently fine-tuning our discovery by testing the potential ameliorative effect of different doses of ketamine in different animal models of depression and anxiety.