Effects of light exposure on amygdala plasticity during adolescence: implications for anxiety and well-being
Anxiety and mood disorders are the most common emotional disorders in adolescents, with suicidal ideation affecting up to 50% of youth. Adolescence is a remarkable period of neuroplasticity in the amygdala, a well-conserved structure best known for its role in emotional behaviors. Although in many cases adaptive, the capacity for neural circuit alteration also induces a state of vulnerability to environmental perturbations.
In modern societies, adolescents are increasingly subjected to irregular environmental lighting, as 80% of adolescents in the USA reported using computers, smartphones, and tablets at night-time. Altered environmental light is associated with impaired mood and an increased risk of psychiatric disorders. An important sub-nucleus of the amygdala, the medial amygdala (MeA) is situated in a crucial position to link environmental lighting to brain regions regulating emotional responses.
Using a translational mouse model, this project explores the effects of alerted patterns of light exposure on amygdala plasticity and emotion-related behavior in adolescent mice, which will potentially lead to new complementary strategies to advance health and well-being in human adolescents.
This project is funded by NIH-NCCIH (K99/R00-AT010903)
Circadian rhythm abnormalities in affective disorders
Depression is one of the most common, disabling, and expensive of all neuropsychiatric disorders. Emerging evidence implicates circadian rhythm abnormalities in the pathophysiology of depression. In particular, the nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in postmortem brains of depressed patients, as well as in stressed mice exhibiting helpless behavior.
We previously found that higher levels of the core circadian clock protein CRYPTOCHROME in the NAc may block D1 dopamine receptor activation during the nocturnal active phase of mice, thereby compromising normal daily activation of NAc neurons and leading to helpless behavior.
This project studies the role of the circadian gene CRYPTOCRHOME in regulating neuronal physiology in the NAc to increase antidepressant efficacy through time dosing administration (chronopharmacology).
In vivo and in vitro pharmacological characterization of novel GABAB receptor allosteric modulators
The GABAB receptor (GABAR), a G protein coupled receptor (GPCR), mediates metabotropic actions of the major inhibitory neurotransmitter GABA in the central nervous system (CNS). GABABRs are widely expressed and distributed in the CNS, and activate several distinct intracellular signal transduction pathways via Gi/o proteins: adenylate cyclase, inhibition and K+ and Ca2+ channel activity modulation. GABABR activity is implicated in a wide range of psychiatric and neurological disorders (i pain, spasticity, anxiety and depression, absence epilepsy, drug addiction, cognition).
Besides the well-known effects of GABABR agonists and antagonists, the recent discovery of allosteric modulators for GABABRs has provided new tools for their pharmacological manipulation offering advantages over hortosteric compounds in terms of selectivity, physicochemical properties and side effects.
This project aims at characterizing new molecules acting as either positive or negative allosteric modulators of the GABABR to improve therapeutic intervention based on GABABR activation or inhibition through allosteric modulation.