Wolterink-Donselaar, I. G.

bioRxiv2024

Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa

Anorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom, which is difficult to control for patients and a major barrier to recovery as it interferes with weight gain. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of the disease and for hyperactivity. At what level the changes in dopamine occur in anorexic states and whether local mesolimbic neurocircuit plasticity is causally involved remains unclear. Especially the role of local GABA control over dopamine neurons, a powerful regulator of the dopamine system, in an AN context is unknown. We hypothesize that combining caloric restriction with exercise, such as in the activity-based anorexia (ABA) model, alters dopamine transmission via GABA disinhibition that, in turn, facilitates the expression of maladaptive behaviors such as hyperactivity. Therefore, we characterized the impact of the ABA model on plasticity of the dopamine reward system. In ex-vivo brain slices of mice exposed to this model, ventral tegmental area dopamine (VTADA) neurons displayed a higher firing frequency compared to control mice supporting that the midbrain dopamine system undergoes plasticity. This coincided with reduced GABAergic transmission on VTADA neurons. This reduction was at least in part attributable to local VTA GABA (VTAGABA) neurons. Indeed, VTAGABA neurons were less excitable, displayed a lower firing frequency and a lower probability of release onto VTADA neurons. Restoring the excitability of VTAGABA neurons via chemogenetic activation rescued mice from starvation, by decreasing running wheel activity. In summary, we found that the anorexic state leads to dysregulation of VTAGABA transmission on VTADA neurons that reinforces maladaptive behaviors such as excessive exercise. We uncovered a new mechanism linked to the disturbed dopamine system in ABA-exposed animals, identifying a hitherto unknown role of decreased local GABAergic control over VTA dopamine neuron output.

neuroscience↗

bioRxiv2023

Neuropeptide Y neurons of the locus coeruleus inhibit noradrenergic system activity to reduce anxiety

Abstract / SummaryAdaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brains main source of noradrenaline and primary mediator of the initial stress response. Built-in systems that exert regulatory control over the LC are largely unidentified. A good candidate system is neuropeptide Y (NPY), which is traditionally linked to anxiety-relief. Currently, the endogenous source of NPY to the LC, and how NPY-expressing neurons modulate the noradrenergic system to regulate anxiety remain unclear. We here identify, in mice, a novel NPY-expressing neuronal population (peri-LCNPY) neighboring LC noradrenergic neurons that locally innervates the pericoerulean space. Moreover, we demonstrate that stress engages peri-LCNPY neurons, increasing their excitability. Mimicking peri-LCNPY neuronal activation using ex vivo chemogenetics suppresses LC noradrenergic neuron activity, via an NPY Y1 receptor-mediated mechanism. Furthermore, in vivo chemogenetic stimulation of peri-LCNPY neurons results in Y1R-dependent anxiety-relief. Conversely, inhibiting peri-LCNPY neurons increases anxiety-like behaviors. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing novel insights in the endogenous mechanisms underlying adaptive responses to adversity.

neuroscience↗