Abstract
Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.
Highlights
Major depression is one of the most common mental disorders
The amplitude of miniature inhibitory postsynaptic currents (IPSCs) was significantly increased in agouti-related protein (AgRP) neurons with a rightshifted cumulative distribution (Fig. 2e1-e2; the cumulative probability of amplitude, Kolmogorov–Smirnov test, D = 0.4542, P < 0.001; amplitude, Mann Whitney test, P = 0.012), while the frequency remained unaltered (Mann Whitney test, P = 0.083). These results demonstrated that chronic unpredictable stress increased inhibitory synaptic transmission onto AgRP neurons
The present study establishes that AgRP neurons in the arcuate nucleus (ARC) are a key component of the neural circuitry underlying depression-related behaviors
Summary
Major depression is one of the most common mental disorders. The lifetime prevalence of depression is 21% among American adults [1], with women having about twice the risk of developing the condition as men. About onethird of patients with major depression can achieve full remission with available treatments. Major depression can cause a variety of symptoms, but anhedonia is one of the two core symptoms required for the diagnosis [2,3,4]. Anhedonia typically does not respond to first-line pharmacotherapies [5, 7, 8] and is usually the last symptom to resolve in depression [9]. It has been considered as a robust predictor of suicidality [10, 11]. The mechanisms underlying the development of hedonic deficits and other key symptoms of depression remain poorly understood
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