Our research mostly revolves around classical neurotransmitters and unconventional transmitters (trophic factors), and how these chemically signaling molecules regulate synaptic communication and information processing in neural circuits. The following projects are currently being pursued in the lab.
Trophic regulation of forebrain cholinergic system and attention in aging and pathological aging
Activation of basal forebrain cholinergic neurons and subsequent release of neurotransmitter acetylcholine in cortex mediates attentional functions. Forebrain cortical cholinergic input system undergoes extensive degeneration in Alzheimer’s disease (AD). Impaired attention hamper information processing in multiple cognitive domains including memory and executive functions and may contribute to functional decline in age-related dementias and AD.Nerve growth factor (NGF) provides trophic support for the survival and maturation of cholinergic neurons through signaling via TrkA (tropomyosin-related kinase A) receptor. NGF produces long-term changes in forebrain cholinergic function. However, signaling mechanisms that link NGF to attentional functions, and how these mechanisms influence attentional information processing during normative aging and pathological aging is not clear. Using AAV-RNAi approaches to produce targeted gene silencing in rats, we are currently exploring the effect of forebrain TrkA receptor knockdown on cortical cholinergic activity and attentional functions during aging. Additionally, we are studying whether developmental disruption of TrkA signaling interacts with chronological aging to accelerate age-related decline in cholinergic transmission and attentional capacities. As abnormal processing of amyloid precursor protein (APP) and cerebral deposition of amyloid-beta (A-beta) is suggested to be an early pathological biomarker for AD, we are also investigating the effects of A-beta oligomers on cholinergic transmission and attentional functions in the absence and presence of pre-existing abnormalities in the forebrain TrkA signaling pathway. These studies will provide insights into neurochemical mechanisms that link amyloidogenic processing of A-beta with the degeneration of forebrain cholinergic circuits and attentional impairments during AD.
Neurochemical substrates of information processing in fronto-striatal circuitsFronto-striatal circuits are linked to various forms of learning and behavioral flexibility. The release of an excitatory neurotransmitter, glutamate, from corticostriatal synapses mediates synaptic plasticity and influences associative learning, memory and executive functions. Brain-derived neurotrophic factor (BDNF) protein exerts neuromodulatory effects on glutamatergic activity and cognitive functions. We seek to understand how BDNF signaling regulates glutamatergic transmission in dorsal striatum and various forms of behavioral flexibility including discrimination learning, reversal learning and set-shifting. As BDNF exerts trophic effects on monoaminergic, specifically dopaminergic neurons, we are also exploring the contribution of striatal dopaminergic inputs to BDNF-induced neuromodulatory effects on striatal glutamate dynamics and cognitive flexibilty. Another related project concerns the impact of psychotropic drugs on neuroadaptive changes in striatal glutamatergic signaling and cognitive control mechanisms subserving adaptive learning. As fronto-striatal circuits are disrupted in neuropsychiatric disorders like Schizophrenia and addiction, these studies have implications in understanding the neurobiology of executive function deficits associated with these mental disorders.