Using complex behavior to understand brain mechanisms in health and disease

At this point in the history of the science of behavior, a focus on neuroscience-based outcomes has become dominant in neuropsychiatric fields at the preclinical and clinical levels of analysis. The notion that behavior is caused by brain function, and that changing brain function can alter behavior, has fueled this push to understand these neurobiological mechanisms. Within this conceptual framework and the funding to incentivize its adoption, the neuroscience field grew rapidly with the goal to understand the relation between the brain and behavior. As such, a reductionist perspective emerged whereby neural manipulations of increasing sophistication became required for assessing the necessity and sufficiency of a particular brain mechanism’s role in behavior (Krakauer et al., 2017). Yet, despite the amazing advances in neuroscience, some, such as the former director of the National Institute of Mental Health, Dr. Thomas Insel, have noted the lack of progress in treatment outcomes for mental illness following the shift in funding from behavioral research to genetics and neuroscience research (Barry, 2022)

Erratum: Author Correction: Midbrain Circuit Regulation of Individual Alcohol Drinking Behaviors in Mice (Nature Communications (2017) 8 1 (2220))

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article

Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

Midbrain circuit regulation of individual alcohol drinking behaviors in mice

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors

Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms

The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine

The effects of ethanol on dopamine terminals in the NAc core and CPu were similar between strains.

<p>DBA and C57 mice had similar dopamine responses to bath applied ethanol in both the NAc core (<b>A</b>) and CPu (<b>B</b>). Furthermore, brain slices from DBA and C57 mice demonstrated similar dopamine clearance rates (tau) in both the NAc core (<b>C</b>) and CPu (<b>D</b>) in the presence of increasing concentrations of ethanol. DA, dopamine.</p

DBA mice exhibited enhanced ethanol-induced locomotor responses.

<p>DBA mice exhibited an enhanced locomotor response over a dose response curve for ethanol, as compared to C57 mice. Data is summed over the first 30 minutes post-ethanol or saline injection. *, p < 0.05; **, p < 0.01; EtOH, ethanol. </p

Dopamine release and clearance in the caudate-putamen (CPu) of DBA and C57 mice.

<p>(<b>A</b>) Raw dopamine traces from the CPu of C57 (left; red) and DBA (right; blue) mice. (<b>B</b>) Strains were similar in electrically evoked dopamine release (left), however DBA mice had a faster tau, indicating increased dopamine clearance (right). (<b>C</b>) The sensitivity of D2-like autoreceptors in the CPu was not different between the two strains. *, p < 0.05; DA, dopamine; Stim, stimulation.</p