Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine.

Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addictive behavior and mood. Presently, it is unknown whether there is a causal link between altered activity in the AcbSh-LH pathway and changes in the motivation for cocaine. In this study, we used an optogenetics approach to either globally stimulate AcbSh neurons or to selectively stimulate AcbSh terminal projections in the LH, in rats self-administering cocaine. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and led to long-lasting facilitation of cocaine-seeking behavior during extinction tests conducted after withdrawal from cocaine self-administration. In contrast, global AcbSh stimulation reduced extinction responding. We compared these opposing motivational effects with effects on mood using the forced swim test, where both global AcbSh neuron and selective AcbSh-LH terminal stimulation facilitated depression-like behavioral despair. Together, these findings suggest that the AcbSh neurons convey complex, pathway-specific modulation of addiction and depression-like behavior, and that these motivation and mood phenomenon are dissociable.

Dehydroepiandrosterone (DHEA) increases territorial song and the size of an associated brain region in a male songbird.

In many species, male territorial aggression is tightly coupled with gonadal secretion of testosterone (T). In contrast, in song sparrows (Melospiza melodia morphna), males are highly aggressive during the breeding (spring) and nonbreeding (autumn and early winter) seasons, but not during molt (late summer). In aggressive nonbreeding song sparrows, plasma T levels are basal (< or = 0.10 ng/ml), and castration has no effect on aggression. However, aromatase inhibitors reduce nonbreeding aggression, indicating a role for estrogen in wintering males. In the nonbreeding season, the substrate for brain aromatase is unclear, because plasma T and androstenedione levels are basal. Aromatizable androgen may be derived from plasma dehydroepiandrosterone (DHEA), an androgen precursor. DHEA circulates at elevated levels in wintering males (approximately 0.8 ng/ml) and might be locally converted to T in the brain. Moreover, plasma DHEA is reduced during molt, as is aggression. Here, we experimentally increased DHEA in wild nonbreeding male song sparrows and examined territorial behaviors (e.g., singing) and discrete neural regions controlling the production of song. A physiological dose of DHEA for 15 days increased singing in response to simulated territorial intrusions. In addition, DHEA treatment increased the volume of a telencephalic brain region (the HVc) controlling song, indicating that DHEA can have large-scale neuroanatomical effects in adult animals. The DHEA treatment also caused a slight increase in plasma T. Exogenous DHEA may have been metabolized to sex steroids within the brain to exert these behavioral and neural effects, and it is also possible that peripheral metabolism contributed to these effects. These are the first results to suggest that exogenous DHEA increases male-male aggression and the size of an entire brain region in adults. The data are consistent with the hypothesis that DHEA regulates territorial behavior, especially in the nonbreeding season, when plasma T is basal.

Seasonal regulation of NMDA receptor NR2B mRNA in the adult canary song system.

Developmental changes in the composition and function of N-methyl-D-aspartate receptors (NMDARs) are believed to regulate neural plasticity. For example, in songbirds, vocal learning entails NMDAR activation, and the sensitive period for such learning in zebra finches (ZFs) parallels developmental changes in NMDAR density and phenotype within several song-related brain regions. In contrast to ZFs, canaries exhibit vocal plasticity recurrently throughout adulthood, prompted by seasonal changes in day length and testosterone (T) levels. We used in situ hybridization to determine if such changes in photoperiod affect NMDAR subunit expression in adult canaries. Birds were sacrificed while on short days (SD) when T levels were low, or on long days (LD) when T levels were high. Transcript levels for the constitutive NMDAR subunit (NR1) and two modulatory subunits (NR2A, NR2B) were measured in four song control nuclei: lMAN, Area X, HVc, and RA. NR1 and NR2A mRNA levels were comparable in SD and LD groups in all four song regions studied. However, NR2B mRNA levels within lMAN and RA were significantly higher in SD than in LD birds. Photoperiod did not affect NR2B transcript levels in Area X, HVc, or a nonsong region just lateral to lMAN. Our data support the hypothesis that changes in NMDAR subunit expression may contribute to the neural and behavioral reorganization that accompanies seasonal song remodeling in adulthood.