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. 2012 Jul 10;109(28):11360-5.
doi: 10.1073/pnas.1209293109. Epub 2012 Jun 25.

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Jennifer L Warner-Schmidt  1 , Eric F Schmidt, John J Marshall, Amanda J Rubin, Margarita Arango-Lievano, Michael G Kaplitt, Ines Ibañez-Tallon, Nathaniel Heintz, Paul Greengard
Affiliations

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Jennifer L Warner-Schmidt et al. Proc Natl Acad Sci U S A. .

Abstract

A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Accumbal cholinergic interneurons express relatively high levels of p11. Colocalization of p11 (red) with choline acetyltransferase (green) in the human nucleus accumbens (A) or the nucleus accumbens of wild-type mice (B). The ChAT positive neuron from the 40× image (white box) is magnified below 4×. (C and D) Colocalization of p11 (red) with medium spiny neuron cell-type markers (green) in the nucleus accumbens of wild-type mice: met-enkephalin, a maker of D2-receptor–containing striatopallidal medium spiny neurons (C), and drd1a, a marker of D1-receptor–containing striatonigral medium spiny neurons (D). Filled arrows indicate a cell that coexpresses p11 and the cell-type marker (ChAT, met-enkephalin, or drd1a); open arrows indicate cells expressing p11 but not the marker. (Scale bars: 20 μm.)
Fig. 2.
Fig. 2.
Cholinergic neurons mediate the effects of p11 on depression-like behaviors. (A) ChAT-, D2-, A2a-, and D1- p11 KO mice were tested for sucrose preference, a model for the hallmark depressive symptom of anhedonia [F(4,107) = 2.578, P < 0.05]. (B) Baseline immobility and the response to citalopram, an SSRI antidepressant, were measured in the tail suspension test in ChAT-, D2-, A2a-, or D1-p11 KO mice [genotype: F(4,111) = 8.604, P < 0.01; citalopram: F(1,111) = 64.5, P < 0.01; interaction: F(4,111) = 0.3805, n.s.]. All data are presented as means ± SEM. Statistically significant effects of genotype (*P < 0.05) or citalopram (#P < 0.05) are noted. n.s., not significant.
Fig. 3.
Fig. 3.
Silencing accumbal cholinergic interneurons causes depression-like behaviors. (A) Immunohistochemical detection of EGFP (green), Cherry (red), and ChAT (blue) in the NAC of a ChAT-CRE positive mouse infected with the AAV-MPE/APC t-toxins mixture. Quantification of the number of ChAT neurons expressing AAV-PE control virus (B) or AAV-MPE/APC viruses (C) indicated near complete infection of ChAT neurons in the NAC by the viruses and no ectopic virus expression in non-ChAT neurons (Results). Mice infected with the AAV-t-toxins (AAV-MPE/APC) or with the AAV-control virus (AAV-PE) were tested in the sucrose preference test [t(16) = 2.259, P < 0.05] (D), the TST [t(18) = 4.095, P < 0.01] (E), the FST [t(18) = 2.565, P < 0.05] (F), or the open field test (G). All data are presented as means ± SEM. *P < 0.05, **P < 0.01.
Fig. 4.
Fig. 4.
Overexpression of p11 in NAc cholinergic interneurons of constitutive p11KO mice restores normal behavior. (A) Schematic of the virus used in these experiments (see text). Constitutive p11 KO mice were bred with ChAT-CRE mice to generate p11 KOs that expressed CRE in ChAT neurons. (B) Immunohistochemical detection of RFP (red), ChAT (blue), and p11 (green) in the NAC of a p11 KO mouse expressing (Upper) or not expressing (Lower) CRE in ChAT neurons. Arrows indicate ChAT-positive cholinergic interneurons overexpressing (Upper) or not over-expressing (Lower) p11. (C–E) Control virus (aav-YFP) or p11 overexpressing virus (aav-p11) was injected to the NAc of CRE-positive WT or p11 KO mice before behavioral testing in the TST [F(1,32) = 6.384, P < 0.05] (C), the sucrose preference test (F(1,32) = 5.681, P < 0.05) (D), or the open field test [main effect AAV: F(1,37) = 3.505, n.s.; main effect genotype: F(1,37) = 0.2654, n.s.] (E). All data are presented as means ± SEM. Significant effects of genotype (#P < 0.05) or p11 overexpression (*P < 0.05, **P < 0.01) are noted. (F–H) CRE-positive constitutive p11KO mice were injected with aav-p11 or aav-YFP into the dorsal striatum (CPU). No effect of p11 overexpression was observed in sucrose preference (main effect virus: F(1,26) = 0.3801, n.s.; main effect genotype: F(1,26) = 1.136, n.s.; interaction virus × genotype: F(1,26) = 0.1272, n.s.) (F), tail suspension test immobility (main effect virus: F(1,25) = 1.994, n.s.; main effect genotype F(1,25) = 1.521, n.s.; Interaction virus × genotype: F(1,25) = 3.874, n.s.) (G), or locomotor activity (main effect virus: F(1,26) ≤0.001, n.s.; main effect genotype: F(1,26) =1.244, n.s.; interaction virus × genotype: F(1,26) = 1.022, n.s.) (H). All data are presented as means ± SEM.
Fig. 5.
Fig. 5.
Circuitry that may mediate depressive-like behaviors and the actions of antidepressants. (A) A simplified summary of the inputs (solid black arrows) and outputs (dashed black arrows) of the NAC (for more detailed anatomy, see Groenwegen et al., 1999). Red arrows indicate cholinergic inputs to these areas, including basal forebrain and pontomesencephalic cholinergic neurons. In the NAC, cholinergic interneurons are the only source of acetylcholine, acting locally within the NAC. (B) In the NAC, there are at least six different cell types. Drd1a containing medium spiny neurons (D1-MSN) and Drd2 containing medium spiny neurons (D2-MSN) are the primary output neurons of the NAC. Cholinergic interneurons (ChAT) and three types of GABAergic interneurons expressing somatostatin/nNOS (SS), parvalbumin (PV), or calretinin (CAL), also reside in the NAC, acting locally to control the activity of the MSNs. AMY, amygdala; DR/LC, dorsal raphe/locus coeruleus; HIP, hippocampus; HYPO, hypothalamus; NAC, nucleus accumbens; PFC, prefrontal cortex; STR, striatum; THAL, thalamus; VP, ventral pallidum; VTA, ventral tegmental area.
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References

    1. Nestler EJ, Carlezon WA., Jr The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151–1159. - PubMed
    1. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192–216. - PMC - PubMed
    1. Wise RA. Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. Trends Neurosci. 2009;32:517–524. - PMC - PubMed
    1. Heller AS, et al. Reduced capacity to sustain positive emotion in major depression reflects diminished maintenance of fronto-striatal brain activation. Proc Natl Acad Sci USA. 2009;106:22445–22450. - PMC - PubMed
    1. Bewernick BH, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010;67:110–116. - PubMed

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