Role of the Brain's Reward Circuitry in Depression: Transcriptional Mechanisms

Abstract

Increasing evidence supports an important role for the brain's reward circuitry in controlling mood under normal conditions and contributing importantly to the pathophysiology and symptomatology of a range of mood disorders, such as depression. Here we focus on the nucleus accumbens (NAc), a critical component of the brain's reward circuitry, in depression and other stress-related disorders. The prominence of anhedonia, reduced motivation, and decreased energy level in most individuals with depression supports the involvement of the NAc in these conditions. We concentrate on several transcription factors (CREB, ΔFosB, SRF, NFκB, and β-catenin), which are altered in the NAc in rodent depression models--and in some cases in the NAc of depressed humans, and which produce robust depression- or antidepressant-like effects when manipulated in the NAc in animal models. These studies of the NAc have established novel approaches toward modeling key symptoms of depression in animals and could enable the development of antidepressant medications with fundamentally new mechanisms of action.

Keywords: BDNF; CREB; Chromatin; Dynorphin; Epigenetics; NFκB; Nucleus accumbens; Ventral tegmental area; β-Catenin; ▵FosB.

Figure 1. The neural circuitry of mood

The figure shows a highly simplified summary of a series of neural circuits in the brain that are believed to contribute to the regulation of mood. While most research in the depression field until recently has focused on hippo-campus (HP) and cerebral cortex (e.g., prefrontal cortex or PFC), there is the increasing realization that several subcortical structures implicated in reward, fear, and motivation are also critically involved. These include the nucleus accumbens (NAc), amygdala (Amy), and hypothalamus (Hypo). The figure shows only a subset of the many known interconnections among these various brain regions. The figure also shows the innervation of several of these brain regions by monoaminergic neurons. The ventral teg-mental area (VTA) provides dopaminergic input to the NAc; inputs to most of the other brain areas are not shown in the figure. Norepinephrine (NE, from the locus coeruleus or LC) and serotonin (5HT from the dorsal raphe and other raphe nuclei) innervate all of the regions shown in the figure. In addition, strong connections between the hypothalamus and VTA–NAc pathway have been established in recent years. From Nestler and Carlezon (2006) with permission.

Figure 2. β-Catenin mediates stress resilience through Dicer1/miRNA regulation

(A) D2-type MSNs are less activated in chronically stressed mice. As a consequence, β-catenin protein remains in the cytoplasm in these cells, unable to enter the nucleus, and the Dicer1 gene is thus inactive. Antiresilience (or prosusceptible) proteins may therefore be produced from mRNAs that would otherwise have been inhibited by miRNAs generated by the DICER1. (B) In resilient mice, β-catenin enters the nucleus of activated D2 MSNs, thereby turning on Dicer1 transcription. Elevated levels of DICER1 increase production of miRNAs and possibly other effectors of resilience. This might, in turn, inhibit the production of antiresilience proteins, because of binding and inhibition of mRNA by miRNAs. From Schratt (2014) with permission.

Figure 3. Examples of chromatin modifications regulated in the NAc by stress or antidepressant treatment

Illustration (top) indicates histone octamers (pink (light gray in the print version)) in heterochromatin (left) and euchromatin (right), along with associated proteins and histone tail/DNA modifications. Table (bottom) lists histone tail modifications of specific residues—depicted on the expanded histone tail illustration (left)—that are regulated by various stress paradigms or antidepressant treatments within the NAc. Arrows indicate an increase (green (light gray in the print version)) or decrease (blue (dark gray in the print version)) in specific modifications. Abbreviations: A, acetylation; P, phosphorylation; M (in a square), histone methylation; M (in a circle), DNA methylation; HAT, histone acetyltransferase; HDAC, histone deacetylase; HMT, histone methyltransferase; pol II, RNA polymerase II. See Peña et al. (2014) for references. Modified from Peña et al. (2014) with permission.

Figure 4. CREB and dynorphin in the NAc in depression

The figure shows a simplified hypothetical scheme by which CREB induction of dynorphin (DYN) in the NAc contributes to certain symptoms of depression. CREB is activated by D1 dopamine receptors (through activation of the cAMP pathway) or by Ca²⁺- or TrkB-regulated signal transduction pathways, which leads to increased expression of DYN. DYN feeds back on κ-opioid receptors located on the terminals and cell bodies/dendrites of VTA dopamine (DA) neurons. Stimulation of these κ receptors inhibits the VTA neurons, which may contribute to anhedonia and related symptoms of depression. Antagonists of κ receptors may thus block the consequences of CREB-induced increases in DYN activity, and exert antidepressant activity in some individuals. From Nestler and Carlezon (2006) with permission.