Progress in understanding mood disorders: optogenetic dissection of neural circuits

Abstract

Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression-like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit-targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depressionrelated behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders.

Neuronal correlates of depression

“…Conversely, the second study showed the opposite effects where phasic activity of VTA DA neurons rescued stress-induced depressive-like behaviour in mice that had undergone chronic mild stress [168]. The discrepancy between the two studies has been discussed [176, 177] and may highlight differential coding processes of VTA DA neurons for strong or weak stressful stimuli [166, 178], which is highly consistent with the fine context-detecting functions of VTA DA neurons [21]. It has recently been shown that rats put through a strong stressful paradigm (restrained stress) exhibited increased firing in the VTA while those through a weaker stress paradigm (mild inescapable stress) exhibited decreased activity [179].…”

Caution When Diagnosing Your Mouse With Schizophrenia: The Use and Misuse of Model Animals for Understanding Psychiatric Disorders

“…Alternative approaches to creating depression-like states, such as social defeat or various chronic stress models, may also be used but are more laborious to implement. Again, one way forward is to connect the behavior with the potential brain circuits (67).…”

Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval

“…The neural circuits underlying the assignment of valence to environmental stimuli are thought to be highly conserved in the mammalian brain (Janak and Tye, 2015) and are dysfunctional in psychopathologies including anxiety, depression and addiction (Allsop et al, 2014; Etkin and Wager, 2007; Lammel et al, 2014; Mervaala et al, 2000; Tye et al, 2011, 2013). Distributed and interconnected brain structures have been tied to valence coding (Berridge and Robinson, 2003; Namburi et al, 2015a; Nieh et al, 2013), but real-time dynamics within circuits processing valence information during behavioral selection remain largely unexplored.…”