Elsevier

Biological Psychiatry

Volume 81, Issue 4, 15 February 2017, Pages 296-305
Biological Psychiatry

Review
Translating the Habenula—From Rodents to Humans

https://doi.org/10.1016/j.biopsych.2016.06.003Get rights and content

Abstract

The habenula (Hb) is a central structure connecting forebrain to midbrain regions. This microstructure regulates monoaminergic systems, notably dopamine and serotonin, and integrates cognitive with emotional and sensory processing. Early preclinical data have described Hb as a brain nucleus activated in anticipation of aversive outcomes. Evidence has now accumulated to show that the Hb encodes both rewarding and aversive aspects of external stimuli, thus driving motivated behaviors and decision making. Human Hb research is still nascent but develops rapidly, alongside with the growth of neuroimaging and deep brain stimulation techniques. Not surprisingly, Hb dysfunction has been associated with psychiatric disorders, and studies in patients have established evidence for Hb involvement in major depression, addiction, and schizophrenia, as well as in pain and analgesia. Here, we summarize current knowledge from animal research and overview the existing human literature on anatomy and function of the Hb. We also discuss challenges and future directions in targeting this small brain structure in both rodents and humans. By combining animal data and human experimental studies, this review addresses the translational potential of preclinical Hb research.

Section snippets

Rodents

Most knowledge on Hb connectivity, as well as structural characteristics and neurochemistry of Hb neurons, stems from studies in animals. In brief, retrograde and anterograde tracing studies in rodents (4, 16) and electrophysiological studies in nonhuman primates (5) have provided a detailed description of afferent and efferent connections of the Hb complex, summarized in Figure 1. Because of their distinct input/output structures, the LHb and MHb seem to form parallel channels, regulating the

Rodents

In animal research, the notion that LHb hyperactivity is associated with depressive-like symptoms, whereas LHb inhibition improves depressive-like behaviors, is well established [reviewed in (12)]. In the late 1980s, a first rat study showed elevated deoxyglucose metabolism in LHb across three behavioral models of depression (27, 28). Among main further findings, an LHb lesion study showed reduced depressive-like behaviors and increased 5-HT turnover in the dorsal raphe nucleus of rats

Rodents

In addiction research, animal studies have been extraordinarily productive to demonstrate the importance of Hb in neuroadaptations to drugs of abuse and negative consequences of drug dependence. Here, we summarize current knowledge with emphasis on recent studies.

Several rodent studies have proposed a role for LHb in cocaine reward and dependence. In a mouse model of cocaine conditioned place preference, c-fos immunohistochemistry showed increased neuronal activation in the LHb of mice

Schizophrenia

Because of the complex connectivity of the Hb to multiple forebrain and hindbrain circuits, similar in rodents, nonhuman primates, and humans, it is anticipated that Hb activity affects multiple dimensions of normal behavior, with implications for disease beyond depression and addiction. Here, we focus on the possible role of the Hb in schizophrenia.

Tightly linked to predicting errors are decision-making processes, and rat studies have demonstrated causal implication of the LHb in subjective

Challenges and Future Directions

In this review, we have organized rodent and human data in three major psychiatric disease areas: depression, drug dependence, and other potential disease areas of psychiatry, notably schizophrenia. We have also added a section on pain in the Supplement. Table 1 summarizes functional consequences of Hb manipulations in both rodents and humans within the four categories.

Basic research in laboratory animals has revealed the Hb as a core integration center, which influences many aspects of

Acknowledgments and Disclosures

This work was supported by the Canada Research Chairs, the Monique H. Bourgeois Chair in Pervasive Developmental Disorders (McGill University), and the National Institutes of Health Grant Nos. NIH-NIAAA 16658 and NIH-NIDA 005010.

We thank Maria Osikowicz for comments and careful reading of the manuscript.

The authors report no biomedical financial interests or potential conflicts of interest.

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