Habenula bibliometrics: Thematic development and research fronts of a resurgent field

Abstract

The habenula (Hb) is a small structure of the posterior diencephalon that is highly conserved across vertebrates but nonetheless has attracted relatively little research attention until the past two decades. The resurgent interest is motivated by neurobehavioral studies demonstrating critical functions in a broad spectrum of motivational and cognitive processes, including functions relevant to psychiatric diseases. The Hb is widely conceived as an "anti-reward" center that acts by regulating brain monoaminergic systems. However, there is still no general conceptual framework for habenula research, and no study has focused on uncovering potentially significant but overlooked topics that may advance our understanding of physiological functions or suggest potential clinical applications of Hb-targeted interventions. Using science mapping tools, we quantitatively and qualitatively analyzed the relevant publications retrieved from the Web of Science Core Collection (WoSCC) database from 2002 to 2021. Herein we present an overview of habenula-related publications, reveal primary research trends, and prioritize some key research fronts by complementary bibliometric analysis. High-priority research fronts include Ventral Pallidum, Nucleus Accumbens, Nicotine and MHb, GLT-1, Zebrafish, and GCaMP, Ketamine, Deep Brain Stimulation, and GPR139. The high intrinsic heterogeneity of the Hb, extensive connectivity with both hindbrain and forebrain structures, and emerging associations with all three dimensions of mental disorders (internalizing, externalizing, and psychosis) suggest that the Hb may be the neuronal substrate for a common psychopathology factor shared by all mental illnesses termed the p factor. A future challenge is to explore the therapeutic potential of habenular modulation at circuit, cellular, and molecular levels.

Keywords: bibliometric; circuit; depression; habenula; p factor; therapeutic target.

FIGURE 1

Number of annual publications on the habenula from 2002 to 2021. Bars represent the annual publication number (left) and line represents the average citation number per year per documents (right).

FIGURE 2

Co-occurrence network analysis of keywords (n = 140) appearing at least 20 times. (A) Classification into five clusters. (B) Average publication year for each cluster.

FIGURE 3

Co-citation network of references. (A) Co-citation map of references on the habenula. (B) Clustered network map of co-cited references on the habenula. (C) Timeline view of co-citation clusters with cluster labels shown on the right.

FIGURE 4

Keywords with the strongest citation bursts in original articles between 2001 and 2021. The timeline is depicted as a year-sliced blue line, and the time interval of a burst is marked as a red section on the blue timeline to indicate the beginning/ending year and the duration of a citation burst.

FIGURE 5

Co-citation analysis of publications from the past 5 years. (A) Co-citation clustering of references on the habenula. (B) The timeline view of co-citation clusters with cluster labels shown on the right.

FIGURE 6

(A) Summary of habenular anatomical circuitry. Inputs and outputs to and from the lateral and medial habenula are shown in red and blue, respectively. (B) Summary of habenular circuits related to different dimensions of psychiatric disorders. Internalizing disorders (such as major depressive disorders and anxiety disorders) are preferentially related to upstream projections to the Hb from the nucleus accumbens (NAc), ventral pallidum (VP), lateral hypothalamus (LH), and lateral preoptic area (LPO), and downstream projections to the rostromedial tegmental nucleus (RMTg), ventral tegmental area (VTA)/substantia nigra pars compacta (SNc), and dorsal raphe nucleus (DRN)/medial raphe nucleus (MRN). Externalizing disorders are exclusively related to the ventral pallidum (VP) and interpeduncular nucleus (IPN). (C) Mechanism for GLT-1 regulation of extracellular glial glutamatergic transmission and LHb neuron bursting. Created with BioRender.com.