A Novel Neural Circuit Saps Pleasure in Model of Depression

Grief is a normal response to some of life’s most powerful stressors – like the death of a loved one, a natural disaster, or a serious break-up. However, this grief may not go away for those suffering from depression. Feelings of helplessness, guilt, and lack of self-worth may stick around for extended periods of time, and a stressor isn’t required to trigger a depressive episode. This description may be familiar to many of us; everyone reading this probably knows someone who has gone through depression. Indeed, according to the World Health Organization, major depressive disorder (the most common clinical diagnosis we commonly refer to as depression) is one of the top 5 leading causes of disability worldwide, and the second most-impactful cause in the United States of America; see (1)). Although depression has an immense impact on patients and their communities, not all individuals respond to currently available antidepressants or psychotherapy. This problem is amplified by the fact that many who once responded to treatment relapse into a depressive episode (2). As neuroscientists, we believe that the brain regulates mental processes and behavior – therefore, mental illnesses have a biological cause in the brain. For example, case studies of patients with damage to the globus pallidus, a brain region involved in movement and reward, exhibit depression-like symptoms after the injury.

In order to investigate the role of the globus pallidus in depression symptoms, Dr. Byungkook Lim’s lab at the University of California – San Diego utilized the best-known mouse model of depression for rigorous investigation. Indeed, much of our understanding of the human brain has come from studying the brains of other mammals such as rodents. While we cannot ask a mouse about its rumination and negative emotions, researchers created mouse models that recapitulate certain aspects of depression. In particular, the model used by Knowland et al., Social Defeat Stress (SDS), induces changes in behavior and neural circuitry that share features with the human condition (3). For example, the stressed mice exhibit anhedonia, a metabolic syndrome, and anxiety-like behaviors, and importantly, antidepressants prescribed to humans reverse many of these changes in mice. The authors begin by studying the basic anatomy with viral approaches such as a rabies virus to trace neuronal connections to targeted cell types. They discovered that interneurons in the Ventral Pallidum (VP) (a sub-region of the globus pallidus) actually send long range projections to the Ventral Tegmental Area (VTA) and Lateral Habenula (LHb) – brain regions implicated in depression and addiction. Unlike the textbook definition of interneurons that release GABA and are therefore inhibitory, they found that many of these “interneurons” are actually excitatory and release glutamate (Fig 1, below).

 (Knowland et al.  Cell  2017)

(Knowland et al. Cell 2017)

These anatomical insights help interpret the main findings of the paper: social defeat stress causes ventral pallidum “interneurons” to become more intrinsically excitable and receive more excitatory inputs as compared to inhibitory. Critically, when the authors decreased the activity of these neurons with 3 different approaches, the mice did not demonstrate depression-like symptoms. Conversely, they expressed a light-sensitive channel in a subset of interneurons and shined a laser to activate these neurons, recreating some of the depression-like symptoms seen after SDS.

These results show that an established mouse model of depression changes the physiological properties of one class of “interneurons” in the ventral pallidum, and these neurons mediate distinct aspects of depression-like behaviors. This brain region could act as a “hub” for the anhedonic symptoms of depression such as less motivation for social interaction and previously pleasurable rewards. Manipulations targeted at modulating this brain region (such as deep brain stimulation or specific drugs) could prove efficacious in the treatment of depression.

1.   T. Vos et al., Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 390, 1211–1259 (2017).

2.   C. Steinert, M. Hofmann, J. Kruse, F. Leichsenring, Relapse rates after psychotherapy for depression – stable long-term effects? A meta-analysis. J. Affect. Disord. 168, 107–118 (2014).

3.   D. Knowland et al., Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of Depression. Cell. 170, 284–297.e18 (2017).