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eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Alex Reichenbach ◽  
Rachel E Clarke ◽  
Romana Stark ◽  
Sarah H Lockie ◽  
Mathieu Mequinion ◽  
...  

Agouti-related peptide (AgRP) neurons increase motivation for food, however whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesized that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 minutes in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.


2021 ◽  
Author(s):  
Stephanie Grella ◽  
Amanda Fortin ◽  
John Bladon ◽  
Leanna Reynolds ◽  
Evan Ruesch ◽  
...  

Abstract Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system, we labeled dorsal dentate gyrus (dDG) neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells were artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory was sufficient to disrupt reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrated operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While interference induced by memory reactivation involved a relatively small set of neurons, we also found that activating a large population of randomly labeled dDG neurons was effective at disrupting reconsolidation. Importantly, reconsolidation-interference was specific to the fear memory. These findings implicate the dDG as a potential therapeutic node for modulating memories to suppress fear.


2021 ◽  
Author(s):  
Stephanie L Grella ◽  
Amanda H Fortin ◽  
John H Bladon ◽  
Leanna F Reynolds ◽  
Evan Ruesch ◽  
...  

Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system, we labeled dorsal dentate gyrus (dDG) neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells were artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory was sufficient to disrupt reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrated operant responding for reactivation of a positive memory, confirming its reward-like properties. These results show that interference from a rewarding experience can counteract negative states. While interference induced by memory reactivation involved a relatively small set of neurons, we also found that activating a large population of randomly labeled dDG neurons was effective at disrupting fear reconsolidation. Importantly, reconsolidation-interference was specific to the fear memory. These findings implicate the dDG as a potential therapeutic node for modulating memories to suppress fear.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Julie A. Meade ◽  
Alison N. Fowlkes ◽  
Mackinsey J. Wood ◽  
Mary Claire Kurtz ◽  
Madeline M. May ◽  
...  

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Sidney Negus ◽  
Amber Baldwin ◽  
Samuel Marsh ◽  
Matthew Banks ◽  
Edward Townsend ◽  
...  

Author(s):  
Miquel Martin ◽  
Miriam Gutiérrez-Martos ◽  
Roberto Cabrera ◽  
Klaus Langohr ◽  
Rafael Maldonado ◽  
...  

ABSTRACT Rationale Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. Objectives Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. Results Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. Conclusions Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.


2021 ◽  
Author(s):  
Alex Reichenbach ◽  
Rachel Clarke ◽  
Romana Stark ◽  
Sarah H Lockie ◽  
Mathieu Mequinion ◽  
...  

Hunger increases the motivation of an organism to seek out and consume highly palatable energy dense foods by acting on the midbrain dopaminergic system. Here, we identify a novel molecular mechanism through which hunger-sensing AgRP neurons detect low energy availability and modulate dopamine release to increase motivation for food reward. We tested the hypothesis that carnitine acetyltransferase (Crat), a metabolic enzyme regulating glucose and fatty acid oxidation, in AgRP neurons is necessary to sense low energy states and regulate motivation for food rewards by modulating accumbal or striatal dopamine release. In support of this, electrophysiological studies show that AgRP neurons require Crat for appropriate glucose-sensing. Intact glucose-sensing in AgRP neurons controls post-ingestive dopamine accumulation in the dorsal striatum. Fibre photometry experiments, using the dopamine sensor GRABDA, revealed that impaired glucose-sensing, in mice lacking Crat in AgRP neurons, reduces dopamine release in the nucleus accumbens to palatable food consumption and during operant responding, particularly in the fasted state. Finally, the reduced dopamine release in the nucleus accumbens of mice lacking Crat in AgRP neurons affects sucrose preference and motivated operant responding for sucrose rewards. Notably, these effects are potentiated in the hungry state and therefore highlight that glucose-sensing by Crat in AgRP neurons is required for the appropriate integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum. These studies offer a novel molecular target to control the overconsumption of palatable foods in a population of hunger-sensing AgRP neurons.


2021 ◽  
Author(s):  
Jared R. Bagley ◽  
Arshad H. Khan ◽  
Desmond J. Smith ◽  
James D. Jentsch

ABSTRACTCocaine self-administration is complexly determined trait, and a substantial proportion of individual differences in cocaine use is determined by genetic variation. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Large and genetically diverse mouse populations, including the Hybrid Mouse Diversity Panel (HMDP), have been developed for forward genetic approaches that can reveal genetic variants that influence traits like cocaine IVSA. This population enables high resolution and well-powered genome wide association studies, as well as the discovery of genetic correlations. Here, we provide information on cocaine (or saline - as a control) IVSA in 65 strains of the HMDP. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near zero to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a very modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced by a substantial proportion of unique genetic variants. These data indicate that the HMDP is suitable for forward genetic approaches for the analysis of cocaine IVSA, and this project has also led to the discovery of reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This is part of an ongoing effort to characterize genetic and genomic variation that moderates cocaine IVSA, which may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.


2021 ◽  
Vol 11 ◽  
Author(s):  
S. Stevens Negus ◽  
S. A. Marsh ◽  
E. A. Townsend

Clinically relevant chronic pain is often associated with functional impairment and behavioral depression as an “affective/motivational” sign of pain; however preclinical animal models of inflammatory and neuropathic pain often produce weak evidence of impaired function. We hypothesized that hindpaw mechanical stimulation produced by a requirement to rear on a textured “NOX” plate would punish operant responding in rats treated with intraplantar complete Freund’s adjuvant (CFA, a model of inflammatory pain) or the chemotherapeutic paclitaxel (PTX, a model of neuropathic pain) and produce sustained pain-related depression of operant behavior. Male Sprague–Dawley rats were trained under a progressive-ratio (PR) schedule of food-maintained operant responding, then treated with CFA (100 µL in left hindpaw), PTX (2.0 mg/kg IP on alternate days for four total injections; 6.6 mg/kg IV on alternate days for three total injections), or saline vehicle. PR break points and mechanical thresholds for paw withdrawal from von Frey filaments were then tracked for 28 days. Subsequently, rats were tested with the opioid receptor antagonist naltrexone to assess latent sensitization and with the kappa opioid receptor (KOR) agonist U69593 to assess KOR function. CFA produced significant mechanical hypersensitivity for 3 weeks but decreased PR breakpoints for only 1 day. Both IP and IV PTX produced mechanical hypersensitivity for at least three weeks; however, only IV PTX decreased PR breakpoints, and this decrease was not alleviated by morphine. After recovery, naltrexone reinstated mechanical hypersensitivity in CFA- but not PTX-treated rats, and it did not reinstate depression of breakpoints in any group. U69593 dose-dependently decreased PR breakpoints in all groups with no difference between control vs. CFA/PTX groups. These results suggest that rearing on a textured NOX plate was not sufficient to punish operant responding in CFA- and PTX-treated rats despite the presence of sustained mechanical hypersensitivity. The rapid recovery of operant responding could not be attributed to latent sensitization, KOR downregulation, or behavioral tolerance. These results extend the range of conditions under which putative chronic pain manipulations produce weak evidence for depression of operant responding as a sign of the “affective/motivational” component of pain in rats.


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