CO-transmission of gaba and glutamate in cortical circuits

The National Institute of Mental Health awarded Massachusetts Eye and Ear Infirmary $666,010 on September 1, 2026, under the Mental Health Research Grants program (CFDA 93.242) to study co-transmission of GABA and glutamate in cortical circuits and the role of neuromodulatory inputs in adult cortical plasticity.

The recipient will employ anatomical circuit tracing, whole-cell electrophysiology, and in vivo two-photon imaging in mouse cortex to investigate how cholinergic and serotonergic neuromodulatory inputs converge onto a unique cortical neuron subtype that co-expresses the vesicular glutamate transporter (VGLUT3) and the vesicular GABA transporter (VGAT). The project will characterize how these neurons release both glutamate and GABA onto specific postsynaptic targets and how this dual release influences cortical processing. The research addresses how neuromodulatory signals conveying information about behavioral state, vigilance, locomotion, and reward acquisition can reawaken adult cortical plasticity—a capability that typically declines after early life but could offer therapeutic pathways to enhance plasticity and treat mental disorders and neurological conditions.

Performance occurs in Boston, MA. The project period runs from September 1, 2026, through May 31, 2031.

Abstract

Neural circuits are remodeled throughout life to adapt to changes in experience and the surrounding environment. Across diverse brain regions, robust rewiring occurs during 'sensitive periods' of development. This plasticity declines precipitously beyond early life, restricting the ability of adults to adjust to new environments and reverse pathological neural activity associated with neurological disorders. However, cortical plasticity can be reawakened in adulthood by neuromodulatory signals that convey information about behavioral state and outcome such as vigilance, locomotion, and the acquisition of rewards. Tapping into the pathways carrying these signals offers a promising avenue to enhance plasticity and treat mental disorders and conditions. Our recent work has identified a unique cortical neuron subtype that is a major target of cholinergic and serotonergic neuromodulatory inputs. Interestingly, these neurons CO-express the vesicular glutamate transporter (VGLUT3) and the vesicular gaba transporter (vgat), suggesting that they have the machinery to release both glutamate and gaba. Here we propose to leverage novel techniques in anatomical circuit tracing, whole-cell electrophysiology and in vivo two-photon imaging in mouse cortex to study how diverse neuromodulatory inputs converge onto this neuronal subtype and how these neurons release gaba and glutamate onto specific postsynaptic targets to influence cortical processing.