Habenula as a Neural Substrate for Aggressive Behavior

Abstract

Over the past decades, an ever growing body of literature has explored the anatomy, connections, and functions of the habenula (Hb). It has been postulated that the Hb plays a central role in the control of the monoaminergic system, thus influencing a wide range of behavioral responses, and participating in the pathophysiology of a number of psychiatric disorders and neuropsychiatric symptoms, such as aggressive behaviors. Aggressive behaviors are frequently accompanied by restlessness and agitation, and are commonly observed in patients with psychiatric disorders, intellectual disabilities, and neurodegenerative diseases of aging. Recently, the Hb has been explored as a new target for neuromodulation therapies, such as deep brain stimulation, with promising results. Here we review the anatomical organization of the habenula and discuss several distinct mechanisms by which the Hb is involved in the modulation of aggressive behaviors, and propose new investigations for the development of novel treatments targeting the habenula to reduce aggressive behaviors.

Nuclei and tracts in the epithalamus of crocodiles

“…It projects to the rostromedial tegmental nucleus, limbic forebrain (lateral hypothalamic area, lateral preoptic area, substantia innominata, and ventrolateral septum), monoaminergic nuclei in the midand hindbrain, several thalamic nuclei (centromedian, parafascicular, mediodorsal, ventrodorsal), superior colliculus, locus coeruleus, and dorsal tegmental area (Bianco & Wilson, 2009;Gouveia & Ibrahim, 2022;Hikosaka, 2010;Namboodiri et al, 2016). These differences are reflected in putative functions of these two parts of the HB.…”

“…In amniotes, the HB is commonly divided into medial and lateral parts (Bianco & Wilson, 2009; Concha & Wilson, 2001). In mammals, where the bulk of studies have been performed, these two divisions differ in their inputs, outputs, and cellular morphology (Bianco & Wilson, 2009; Gouveia & Ibrahim, 2022; Hikosaka, 2010; Namboodiri et al., 2016). The medial habenula (HbM) receives afferents from the supracommissural septum, diagonal band of Broca, lateral preoptic area, monoaminergic nuclei, ventral tegmental area, and the locus coeruleus and sends efferents to the interpeduncular nucleus.…”

“…On the other hand, the lateral habenula (HbL) has inputs from basal ganglia (globus pallidus and its equivalents), lateral hypothalamus, lateral preoptic area, diagonal band of Broca, suprachiasmatic nucleus, monoaminergic cells, median raphe, locus coeruleus, and ventral tegmental area. It projects to the rostromedial tegmental nucleus, limbic forebrain (lateral hypothalamic area, lateral preoptic area, substantia innominata, and ventrolateral septum), monoaminergic nuclei in the mid‐ and hindbrain, several thalamic nuclei (centromedian, parafascicular, mediodorsal, ventrodorsal), superior colliculus, locus coeruleus, and dorsal tegmental area (Bianco & Wilson, 2009; Gouveia & Ibrahim, 2022; Hikosaka, 2010; Namboodiri et al., 2016). These differences are reflected in putative functions of these two parts of the HB.…”

Habenula activation patterns in a preclinical model of neuropathic pain accompanied by depressive-like behaviour

“…The habenula (Hb), an epithalamic structure of the limbic system, plays a key role in the endocrine system, reward, addiction, pain, and depressive behaviours [12,13,18]. The Hb can be divided into lateral (LHb) and medial (MHb) parts, based on cell type and connectivity pattern [19,20]. The LHb can be further subdivided into lateral (LHbL) and medial (LHbM) regions, while the MHb can be parcellated into superior (MHbS), inferior (MHbI), central (MHbC), and lateral (MHbL) regions [20][21][22][23].…”

“…The Hb can be divided into lateral (LHb) and medial (MHb) parts, based on cell type and connectivity pattern [19,20]. The LHb can be further subdivided into lateral (LHbL) and medial (LHbM) regions, while the MHb can be parcellated into superior (MHbS), inferior (MHbI), central (MHbC), and lateral (MHbL) regions [20][21][22][23]. The LHb sends several outputs to the raphe nuclei and ventral tegmental area [24], which are strongly related to analgesia [25] and have been proposed to play a prominent role in pain processing [26,27], and in depressive-like behaviours in models of neuropathic pain [15,28,29].…”