The molecular and cellular mechanisms of depression: a focus on reward circuitry

Abstract

Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.

Fig. 1

Stress alters ventral tegmental area dopamine neurons to generate depressive behavior. Top: Simplified schematic of ventral tegmental area (VTA) projections associated with stress susceptibility. Inhibition of the VTA to prefrontal cortex (PFC) projection is pro-depressant. Stimulation of the VTA to nucleus accumbens (NAc) projection is pro-depressant. Noradrenergic neurons from the locus coeruleus (LC) project to the VTA where they modulate excitability and stress-susceptibility. Middle: VTA dopamine neuron firing is increased in mice susceptible to social defeat (CSDS) and decreased after chronic unpredictable stress (CUS). Excitability of VTA dopamine neurons is modulated by norepinephrine through α₁ and β₃ receptors (brown), acetylcholine through muscarinic receptors (pink), and a balancing of I_h and K⁺ currents through HCN (orange) and KCNQ channels (purple). Inset box details genes associated with stress susceptibility in the VTA. Bottom: Dopamine varicosity (green) releasing dopamine in the NAc. Stress is associated with greater phasic dopamine release, upregulation of dopamine transporters (DAT), dopamine receptors, and BDNF-TrkB signaling

Fig. 2

Depression is associated with cell-type-specific adaptations to nucleus accumbens medium-spiny neurons. Top, upper left: Susceptibility to social defeat stress is associated with a weakening of gluta-matergic inputs from prefrontal cortex (PFC) and strengthening of inputs from intralaminar thalamus (ILT) and ventral hippocampus (vHPC) to nucleus accumbens medium-spiny neurons (NAc MSNs). Top, lower left: Stress-susceptible mice have increased expression of glutamate transporter Vglut2, increased calcium-permeable AMPA receptors (red), and increased GluN2B containing NMDA receptors (blue). Top, right: Cholinergic interneurons (ChI) have reduced protein p11 and ChI inhibition induces depressive behavior. Middle: Genes associated with stress susceptibility in the NAc. Bottom, left: In stress-susceptible mice, dopamine D1 receptor expressing MSNs undergo dendritic atrophy. D1-MSNs also have decreased excitatory input, increased intrinsic excitability, and reduced activity in vivo. Neuroligin-2 (NLGN-2) expression is decreased selectively in D1-MSNs. Sirtuin-1 (SIRT1), Early Growth Response 3 (Egr3), and RhoA expression are increased selectively in D1-MSNs. Inset: Egr3 transcriptionally regulates expression of RhoA in stress-susceptible mice. Bottom, right: In stress-susceptible mice, dopamine D2 receptor expressing MSNs do not undergo dendritic atrophy, but may increase spine density. D2-MSNs have increased excitatory input. β-catenin (CTNNB1) and transporter Slc6a15 expression are reduced selectively in D2-MSNs