Biology subjects

Becker-Krail, D.

Publications and source records attributed to Becker-Krail, D..

3 recordsLinked to original sources

bioRxiv2023

Differential Effects of Cocaine and Morphine on the Diurnal Regulation of the Mouse Nucleus Accumbens Proteome

Substance use disorders (SUDs) are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based (LC-MS/MS) quantitative proteomics, along with a data-independent acquisition (DIA) analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveals cocaine and morphine differentially alters diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome.

neuroscience↗

bioRxiv2020

The Suprachiasmatic Nucleus Regulates Anxiety-Like Behavior in Mice

Circadian rhythms are commonly disrupted in individuals with depression and/or anxiety disorders. Animal studies indicate that circadian rhythm disruption can cause increased depressive and anxiety-like behavior, but the underlying mechanisms are unclear. Currently, there is conflicting evidence as to whether the master pacemaker in the brain, the suprachiasmatic nucleus (SCN), plays a key role in regulating psychiatric-related behavior. To investigate the role of the SCN in regulating depressive and anxiety-like behavior in mice, we directly manipulated the neural activity of the SCN using two chronic optogenetic stimulation paradigms. Repeated stimulation of the SCN late in the active phase (circadian time 21, CT21) shortened the period and dampened the amplitude of homecage activity rhythms. Repeated stimulation of the SCN at unpredictable times during the dark phase dampened, fragmented and reduced the stability of homecage activity rhythms. In both SCN optogenetic stimulation paradigms, dampened homecage activity rhythms (decreased amplitude) was associated with increased measures of anxiety-like behavior, but not in control mice. Increased fragmentation and decreased day-to-day stability of homecage activity also correlated with increased anxiety-like behavior. Unexpectedly the change in period of homecage activity rhythms was not directly associated with any psychiatric-related behavior. Furthermore, we did not observe consistent correlations between homecage activity amplitude and depressive-like behavior in stimulated mice. Taken together, these results indicate that SCN-mediated dampening of rhythms is directly correlated with increased anxiety-like, but not depressive-like behavior in mice. This work is an important step in understanding how specific SCN neural activity disruptions affect mood and anxiety-related behavior.

neuroscience↗

bioRxiv2019

Circadian- and sex-dependent increases in intravenous cocaine self-administration in Npas2 mutant mice

Substance use disorder is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine reinforcement was increased in all Npas2 mutants, while self-administration and motivation were affected sex-dependently. These sex differences were amplified during the dark (active) phase with Npas2 mutation increasing self-administration, reinforcement, motivation, extinction responding and reinstatement in females, but only reinforcement in males. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in Npas2 mutant females, we measured cocaine-induced {Delta}FosB expression. Relative to WT, {Delta}FosB expression was increased in D1+ neurons in the nucleus accumbens core and dorsolateral striatum in Npas2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in Npas2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of Npas2 mutation in females. Significance StatementCircadian disruptions are a common symptom of substance use disorders and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent substance use. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to substance use vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor NPAS2 is enriched in reward-related brain regions and regulates reward, but its role in substance use is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type and Npas2 mutant mice at different times of day.

neuroscience↗