Synaptic Neuromodulation

Neuromodulators expand the abilities of neuronal networks to process information and to perform fine-tuning computations that impact cognition, emotion, and behavior. Despite their key role, the molecular mechanisms orchestrating neuromodulatory function in the central nervous system (CNS) are much more unknown than those of inhibitory or excitatory transmission.

Our laboratory is interested in understanding the function of hypothalamic circuits, as major regulators of neuromodulation in the CNS. In particular, we are focused on the oxytocin (OXT) and vasopressin (VSP) systems, two neuropeptides involved in a myriad of homeostatic functions like stress regulation and energy balance as well as complex behaviors such as social interaction. We have implemented novel state-of-the-art imaging techniques (Light Sheet Microscopy) in combination with behavioral assays and electrophysiological methods to explore the functional properties of these circuits, from their development to their decline during natural and pathological conditions like neurodegenerative disorders.

We currently work on three research lines:

1. Release of hypothalamic neuropeptides. We employ live cell imaging technologies to investigate the mechanisms underlying neuropeptide-containing vesicle dynamics and release. Our results indicate OXT exocytosis is regulated by specific SNARE molecules, which provide new targets to modulate OXT levels in vitro and in vivo.

2. Development, specification, and plasticity of hypothalamic circuits. Our group employs novel brain clarification techniques such as iDISCO+ and electrophysiology to examine the specification of neuromodulatory circuits and their plastic adaptations during adulthood and aging.

3. Impact of natural aging and neurodegeneration on social behavior. Agitation and social anxiety are common Alzheimer´s disease symptoms even in the early stages of the disease, indicating a malfunction of hypothalamic circuits involved in stress and social responses. Thus, a major focus of our group is to understand how hypothalamic circuits (OXT-VSP systems) are affected by both natural and pathological aging, and how these alterations may impact the social behavior of aged subjects.

Following our recent work (Portalés et al., 2023), we are currently studying the potential causal relationship between age-related social deficits such as social anxiety and the dysfunction of the oxytocinergic system, with the overarching goal of providing molecular targets to ameliorate the consequences of this understudied aspect of both natural and pathological aging.