Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

Anxiety commonly co‐occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Anxiety disorders and obsessive-compulsive disorder (OCD) are disabling psychiatric conditions and the major contributors to global burden of nonfatal illness (1). OCD is characterized by recurrent thoughts (obsessions) and/or repetitive behaviors (compulsions) that are aimed at reducing the anxiety caused by obsessions (2, 3), indicating a close correlation between anxiety and OCD. Indeed, anxiety disorders have been reported epidemiologically as the most frequent comorbid conditions with OCD (3, 4). Therefore, common pathologies may be present in anxiety disorders and OCD, and elucidation of the shared neural substrates will lead to greater insight into their pathophysiology and treatment.The nucleus accumbens (NAc) is a main component of the ventral striatum and a pivotal node in limbic basal ganglia loop, whose dysfunction may result in psychiatric diseases such as anxiety and OCD (5, 6). Accumulating experimental and clinical evidence indicates that the NAc, particularly the core compartment, holds a key position in motivation, emotion, and cognition and is strongly implicated in the psychopathology and treatment of anxiety and OCD. It has been reported that trait anxiety and OCD risk are positively correlated with the volume of NAc (7, 8). Functional neuroimaging reveals that the NAc activation correlates positively with the severity of human anxiety and obsessive-compulsive symptoms in OCD patients (9, 10). More importantly, deep brain stimulation (DBS) targeting the NAc core has been found to improve obsessive-compulsive symptoms and decrease ratings of anxiety in patients suffering from treatment-resistant OCD or depression (11, 12). Therefore, NAc core may be a potential common neural substrate for the clinical and neuropathological overlap between anxiety and OCD.The NAc core receives dense glutamatergic projections from the limbic system, including the prefrontal cortex, basolateral amygdala (BLA), and ventral hippocampus (vHipp), and integrates cognitive and affective information to instigate motivational approach behaviors (13, 14). In addition, the NAc core is regulated by various neuromodulators, such as orexin, serotonin, and histamine, from several brain regions (15–17). Among them, central histamine is synthesized and released by the histaminergic neurons restrictedly concentrated in the tuberomammillary nucleus (TMN) of the hypothalamus and serves as a general modulator for whole-brain activity via the mediation of histamine H1 to H4 receptors (18, 19). Accordingly, the aberrant histamine signaling is closely associated with sleep, motor, cognitive, and psychiatric conditions (18, 20, 21). In the clinic, drugs targeting the presynaptic H3 receptor have been used for prescribed treatment of various psychiatric and neurologic disorders (22). Interestingly, a high density of the H3 receptor has been found in NAc (23, 24). Therefore, in the present study, we create a transgenic rat strain expressing Cre recombinase in histidine decarboxylase (HDC, the histamine-synthesizing enzyme) neurons and employ anterograde axonal tract tracings, whole-cell patch clamp recordings, optogenetic and chemogenetic manipulation, and behavioral tests to explore the role of hypothalamic histaminergic afferents and the H3 receptor in the NAc core in regulation of anxiety and obsessive-compulsive-like behaviors. We find that optogenetic activation of hypothalamic TMN–NAc core histaminergic projections produces an anxiolytic effect and ameliorates obsessive-compulsive-like behaviors induced by restraint stress, which is due to H3 receptor–mediated suppression of glutamatergic transmission in a common prelimbic prefrontal cortex (PrL)–NAc core pathway.