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1.
J Neurosci ; 2024 Sep 26.
Article in English | MEDLINE | ID: mdl-39327005

ABSTRACT

The prefrontal cortex is critical for decision-making across species, with its activity linked to choosing between options. Drift Diffusion Models (DDMs) are commonly employed to understand the neural computations underlying this behavior. Studies exploring the specific roles of regions of the rodent prefrontal cortex in controlling the decision process are limited. This study explored the role of the prelimbic cortex (PLC) in decision-making using a two-alternative forced-choice task. Rats first learned to report the location of a lateralized visual stimulus. The brightness of the stimulus indicated its reward value. Then, the rats learned to make choices between pairs of stimuli. Sex differences in learning were observed, with females responding faster and more selectively to high-value stimuli than males. DDM analysis found that males had decreased decision thresholds during initial learning, whereas females maintained a consistently higher drift rate. Pharmacological manipulations revealed that PLC inactivation reduced the decision threshold for all rats, indicating that less information was needed to make a choice in the absence of normal PLC processing. Mu opioid receptor stimulation of the PLC had the opposite effect, raising the decision threshold and reducing bias in the decision process towards high-value stimuli. These effects were observed without any impact on the rats' choice preferences. Our findings suggest that PLC has an inhibitory role in the decision process and regulates the amount of evidence that is required to make a choice. That is, PLC activity controls "when", but not "how", to act.Significance Statement This study reports causal evidence for a part of the rat prefrontal cortex, the prelimbic cortex, in controlling the amount of information needed to make a choice. Results were based on reversible inactivation using the GABA-A agonist muscimol and by stimulation of mu opioid receptors using intra-cortical infusions of the selective mu agonist DAMGO. We also found evidence for a sex difference in learning and performing a visually guided two-alternative forced-choice task. Drift Diffusion Models found that females had stable decision processes throughout learning, and showed a persistent bias against the lower value option. By contrast, males exhibited changes in their decision processes, notably reducing the amount of information needed to make choice over the period of early choice learning.

2.
Future Oncol ; 18(1): 105-115, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34763531

ABSTRACT

Supplies of intravesical Bacillus Calmette-Guérin (BCG), the first-line treatment for most intermediate- and high-risk non-muscle-invasive bladder cancers (NMIBC), have proven unreliable over the past decade. This review considers the evolution of BCG immunotherapy for NMIBC: from the discovery of the antitumour side effects of tuberculosis and subsequently the BCG vaccine, to recent advances in novel immunotherapeutic agents. We summarize the evidence for alternative options to standard intravesical BCG therapy regimens and describe the potential for immune response manipulating drugs in the treatment of NMIBC. These new agents, including immune checkpoint inhibitors, toll-like receptor agonists and recombinant viral vectors, may provide better options in the management of NMIBC in the future.


Lay abstract Many patients with non-invasive bladder cancers may need treatments into the bladder, including one called Bacillus Calmette-Guérin (BCG). Unfortunately, the supplies of BCG have been interrupted and somewhat unreliable since 2012. Because of this, we have been forced to look at other means of treating our patients using drugs similar to BCG. This has made us think about how BCG treatment was first developed more than 40 years ago and how it has evolved as a treatment for bladder cancer. In this article, we review the current uses of BCG and other treatments for bladder cancer and explore what the future may hold for bladder cancer treatment.


Subject(s)
BCG Vaccine/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Toll-Like Receptors/agonists , Urinary Bladder Neoplasms/drug therapy , Humans , Mitomycin/therapeutic use
3.
Appetite ; 175: 106037, 2022 Aug 01.
Article in English | MEDLINE | ID: mdl-35429580

ABSTRACT

This research aimed to understand the consumption practices of plant-based meat substitutes (PBMS). Semi-structured in-depth interviews were conducted with consumers and Social Practice Theory (SPT) was adopted as the theoretical framework to explore emerging themes relating to consumer practices. Findings indicate that consumers engage in a number of related practices that include the acquisition, preparation, and consumption of PBMS which were embedded within a larger network of practices that included storage, substitution, and food safety, as well as broader meat-based, meat-free, plant-based, and social and cultural practices. This paper highlights the importance of social and cultural structures in facilitating product awareness, and meaning and skill development in the context of dietary and behavioural change. Implications for research, marketing, and policymaking practices are discussed with regard to the marketing of plant-based meat substitutes as well as shifting consumer behaviour.

4.
J Fish Dis ; 45(11): 1721-1731, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36017570

ABSTRACT

Epitheliocystis, an intracellular bacterial infection in the gills and skin epithelium, has been frequently reported in Atlantic salmon (Salmo salar) during freshwater production in a number of countries. This study describes the prevalence and intensity of a natural epitheliocystis infection present in the gills of two strains of Atlantic salmon reared in either a flow-through (FT) or a recirculation aquaculture system (RAS) in Ireland. Repeated sampling of gills prior to and throughout seawater transfer, histology and quantitative real-time PCR were used to determine infection prevalence and intensity. Despite no clinical gill disease, and minor histopathological changes, epitheliocystis lesions were identified in histology at all time points. Specific PCR confirmed the presence of Candidatus Clavichlamydia salmonicola in both strains and its number of copies was correlated with intensity of epitheliocystis lesions. A significant interaction between hatchery system and fish strain on the prevalence and intensity of gill epitheliocystis was found both using histological and molecular methods. Specifically, fish from FT had higher prevalence and intensity than RAS reared fish and within FT, the Irish cohort were more affected than Icelandic.


Subject(s)
Bacterial Infections , Fish Diseases , Salmo salar , Animals , Aquaculture , Bacterial Infections/veterinary , Fish Diseases/microbiology , Fresh Water , Gills/pathology , Prevalence
5.
Plant Dis ; 106(10): 2678-2688, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35196102

ABSTRACT

The wheat curl mite (WCM) is a vector of three important wheat viruses in the U.S. Great Plains: wheat streak mosaic virus (WSMV), triticum mosaic virus (TriMV), and High Plains wheat mosaic virus (HPWMoV). This study was conducted to determine the current profile of WCM and WCM-transmitted viruses of wheat and their occurrence in Colorado, including novel wheat viruses via virome analysis. There was a high rate of virus incidence in symptomatic wheat samples collected in 2019 (95%) and 2020 (77%). Single infection of WSMV was most common in both years, followed by coinfection with WSMV + TriMV and WSMV + HPWMoV. Both type 1 and type 2 mite genotypes were found in Colorado. There was high genetic diversity of WSMV and HPWMoV isolates, whereas TriMV isolates showed minimal sequence variation. Analysis of WSMV isolates revealed novel virus variants, including one isolate from a variety trial, where severe disease symptoms were observed on wheat varieties carrying Wsm2, a known virus resistance locus. Virome analysis identified two to four sequence variants of all eight RNA segments of HPWMoV, which suggests co-occurrence of multiple genotypes within host populations and presence of a variant of HPWMoV. A possible novel virus in the family Tombusviridae and several mycoviruses were identified. Overall, the data presented here highlight the need to define the effect of novel WCM-transmitted virus variants on disease severity and the role of novel viruses.


Subject(s)
Mites , Potyviridae , Animals , Colorado , Mites/genetics , Plant Diseases , Potyviridae/genetics , RNA , Virome
6.
Appetite ; 160: 105073, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33359236

ABSTRACT

Meat reduction has important implications for public health and the environment. With people more likely to reduce their meat consumption than eliminate it completely, there is increased interest in flexitarian (reduced meat) diets. Young adults in particular are transitioning towards a flexitarian diet, yet there is very little research on this crucial sub-set of the population. In this research, 23 interviews are conducted with young adults aged 18-35 in New Zealand to explore their lived experiences (i.e., motivations, strategies and barriers) towards flexitarianism. The research finds young adults are encouraged to transition towards flexitarianism due to increased control, through a transition away from home which is enabled through cooking strategies, social support and experimentation. Young flexitarians are motivated to reduce meat consumption due to concern about various individual (health, variety, price, reduce social unease) and altruistic (environment and ethics) motivations. Continued meat consumption is mainly driven by a need to compromise at social gatherings, and due to positive associations with variety, nutrients and fullness as well as taste due to cravings. The findings have several implications for social marketing and public health, particularly around supportive social settings, seeing flexitarianism as a 'not all or nothing approach' (one does not have to be a full vegetarian or a meat eater, but can instead be something in between), positive emotions such as pride associated with meat reduction, and that documentaries and social networks are key triggers for meat reduction.


Subject(s)
Diet , Meat , Humans , Motivation , New Zealand , Vegetarians , Young Adult
8.
J Neurosci ; 39(42): 8275-8284, 2019 10 16.
Article in English | MEDLINE | ID: mdl-31619497

ABSTRACT

The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.


Subject(s)
Neurosciences/methods , Research , Technology , Humans
9.
J Neurosci ; 38(29): 6427-6438, 2018 07 18.
Article in English | MEDLINE | ID: mdl-29921715

ABSTRACT

The BRAIN Initiative arose from a grand challenge to "accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought." The BRAIN Initiative is a public-private effort focused on the development and use of powerful tools for acquiring fundamental insights about how information processing occurs in the central nervous system (CNS). As the Initiative enters its fifth year, NIH has supported >500 principal investigators, who have answered the Initiative's challenge via hundreds of publications describing novel tools, methods, and discoveries that address the Initiative's seven scientific priorities. We describe scientific advances produced by individual laboratories, multi-investigator teams, and entire consortia that, over the coming decades, will produce more comprehensive and dynamic maps of the brain, deepen our understanding of how circuit activity can produce a rich tapestry of behaviors, and lay the foundation for understanding how its circuitry is disrupted in brain disorders. Much more work remains to bring this vision to fruition, and the National Institutes of Health continues to look to the diverse scientific community, from mathematics, to physics, chemistry, engineering, neuroethics, and neuroscience, to ensure that the greatest scientific benefit arises from this unique research Initiative.


Subject(s)
Brain Mapping/methods , Neurosciences/methods , Animals , Humans , National Institutes of Health (U.S.) , United States
10.
Eur J Neurosci ; 49(9): 1115-1126, 2019 05.
Article in English | MEDLINE | ID: mdl-30565761

ABSTRACT

Our previous work indicated that male, but not female, offspring of cocaine-experienced sires display blunted cocaine self-administration. We extended this line of investigation to examine behavioral sensitization, a commonly used model of cocaine-induced behavioral and neuronal plasticity. Results indicated that male, but not female, offspring of cocaine-taking sires showed deficits in the ability of repeated systemic cocaine injections to induce augmented locomotor activity. The reduced cocaine sensitization phenotype in male progeny was associated with changes in histone post-translational modifications, epigenetic processes that regulate gene expression by controlling the accessibility of genes to transcriptional machinery, in the nucleus accumbens of first-generation male progeny. Thus, five histone post-translational modifications were significantly altered in the male progeny of cocaine-exposed sires. In contrast, self-administration of nicotine was unaltered in male and female offspring suggesting that the intergenerational effects of paternal cocaine taking may be drug-specific. Interestingly, the reduced sensitivity to cocaine previously observed in the male offspring of cocaine-taking sires dissipated in the grand-offspring. Both male and female grand-progeny of cocaine-exposed sires showed unaltered cocaine-induced behavioral sensitization and cocaine self-administration. Taken together, these findings indicate that paternal cocaine taking produces changes in multiple cocaine addiction-related behaviors in male progeny, which do not persist beyond the first generation of offspring. Moreover, the altered sensitivity to cocaine in first-generation male progeny of cocaine-sired male offspring was associated with epigenetic modifications in the nucleus accumbens, a nucleus that plays a critical role in cocaine-associated behavioral plasticity.


Subject(s)
Behavior, Animal/drug effects , Cocaine/toxicity , Dopamine Uptake Inhibitors/toxicity , Neuronal Plasticity/drug effects , Paternal Exposure/adverse effects , Sex Characteristics , Animals , Female , Male , Pregnancy , Prenatal Exposure Delayed Effects/etiology , Rats , Rats, Sprague-Dawley
11.
Int J Mol Sci ; 20(4)2019 Feb 23.
Article in English | MEDLINE | ID: mdl-30813401

ABSTRACT

The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the direct downstream effector of Ras-extracellular signal-regulated kinase (ERK1/2) signalling. ERK1/2 activation directly phosphorylates and activates p90RSK, which, in turn, activates various signalling events through selection of different phosphorylation substrates. Upregulation of p90RSK has been reported in numerous human diseases. p90RSK plays an important role in the regulation of diverse cellular processes. Thus, aberrant activation of p90RSK plays a critical role in the pathogenesis of organ dysfunction and damage. In this review, we focus on the current understanding of p90RSK functions and roles in the development and progression of kidney diseases. Roles of p90RSK, as well as other RSKs, in cardiovascular disorders and cancers are also discussed.


Subject(s)
Kidney Diseases/enzymology , Kidney Diseases/pathology , Kidney/enzymology , Kidney/pathology , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Animals , Cardiovascular Diseases/enzymology , Humans , Neoplasms/enzymology , Signal Transduction
12.
Fish Physiol Biochem ; 44(1): 119-135, 2018 Feb.
Article in English | MEDLINE | ID: mdl-28894993

ABSTRACT

Growth hormone (GH) transgenic (T) coho salmon consistently show remarkably enhanced growth associated with increased appetite and food consumption compared to non-transgenic wild-type (NT) coho salmon. To improve understanding of the mechanism by which GH overexpression mediates food intake and digestion in T fish, feed intake and gastric evacuation rate (over 7 days) were measured in size-matched T and NT coho salmon. T fish displayed greatly enhanced feed intake levels (~ 2.5-fold), and more than 3-fold increase in gastric evacuation rates relative to NT coho salmon. Despite the differences in feed intake, no differences were noted in the time taken from first ingestion of food to stomach evacuation between genotypes. These results indicate that enhanced feed intake is coupled with an overall increased processing rate to enhance energy intake by T fish. To further investigate the molecular basis of these responses, we examined the messenger RNA (mRNA) levels of several genes in appetite- and gastric-regulation pathways (Agrp1, Bbs, Cart, Cck, Glp, Ghrelin, Grp, Leptin, Mc4r, Npy, and Pomc) by qPCR analyses in the brain (hypothalamus, preoptic area) and pituitary, and in peripheral tissues associated with digestion (liver, stomach, intestine, and adipose tissue). Significant increases in mRNA levels were found for Agrp1 in the preoptic area (POA) of the brain, and Grp and Pomc in pituitary for T coho salmon relative to NT. Mch and Npy showed significantly lower mRNA levels than NT fish in all brain tissues examined across all time-points after feeding. Mc4r and Cart for T showed significantly lower mRNA levels than NT in the POA and hypothalamus, respectively. In the case of peripheral tissues, T fish had lower mRNA levels of Glp and Leptin than NT fish in the intestine and adipose tissue, respectively. Grp, Cck, Bbs, Glp, and Leptin in stomach, adipose tissue, and/or intestine showed significant differences across the time-points after feeding, but Ghrelin showed no significant difference between T and NT fish in all tested tissues.


Subject(s)
Animals, Genetically Modified , Gastrointestinal Transit/genetics , Growth Hormone/genetics , Oncorhynchus kisutch/genetics , Animals , Digestion/physiology , Feeding Behavior/physiology , Gastrointestinal Transit/physiology , Genotype , Growth Hormone/metabolism , Oncorhynchus kisutch/physiology
13.
Ann Surg Oncol ; 23(6): 2070-8, 2016 06.
Article in English | MEDLINE | ID: mdl-26895751

ABSTRACT

BACKGROUND: Sentinel lymph node biopsy (SLNB) in melanoma is currently performed using the standard dual technique (radioisotope and blue dye). The magnetic technique is non-radioactive and provides a brown color change in the sentinel lymph node (SLN) through an intradermal injection of a magnetic tracer, and utilizes a handheld magnetometer. The MELAMAG Trial compared the magnetic technique with the standard technique for SLNB in melanoma. METHODS: Clinically node-negative patients with primary cutaneous melanoma were recruited from four centers. SLNB was undertaken after intradermal administration of both the standard (blue dye and radioisotope) and magnetic tracers. The SLN identification rate per patient, with the two techniques, was compared. RESULTS: A total of 133 patients were recruited, 129 of which were available for final analysis. The sentinel node identification rate was 97.7 % (126/129) with the standard technique and 95.3 % (123/129) with the magnetic technique [2.3 % difference; 95 % upper confidence limit (CL) 6.4; 5.4 % discordance]. With radioisotope alone, the SLN identification rate was 95.3 % (123/129), as with the magnetic technique (0 % difference; 95 % upper CL 4.5; 7.8 % discordance). The lymph node retrieval rate was 1.99 nodes per patient overall, 1.78 with the standard technique and 1.87 with the magnetic technique. CONCLUSIONS: The magnetic technique is feasible for SLNB in melanoma with a high SLN identification rate, but is associated with skin staining. When compared with the standard dual technique, it did not reach our predefined non-inferiority margin.


Subject(s)
Coloring Agents , Magnets , Melanoma/pathology , Sentinel Lymph Node Biopsy , Sentinel Lymph Node/pathology , Aged , Feasibility Studies , Female , Follow-Up Studies , Humans , International Agencies , Male , Melanoma/surgery , Middle Aged , Prognosis , Sentinel Lymph Node/surgery
14.
Horm Behav ; 84: 18-28, 2016 08.
Article in English | MEDLINE | ID: mdl-27149948

ABSTRACT

Survival, competition, growth and reproductive success in fishes are highly dependent on food intake, food availability and feeding behavior and are all influenced by a complex set of metabolic and neuroendocrine mechanisms. Overexpression of growth hormone (GH) in transgenic fish can result in greatly enhanced growth rates, feed conversion, feeding motivation and food intake. The objectives of this study were to compare seasonal feeding behavior of non-transgenic wild-type (NT) and GH-transgenic (T) coho salmon (Oncorhynchus kisutch), and to examine the effects of intraperitoneal injections of the appetite-regulating peptides cholecystokinin (CCK-8), bombesin (BBS), glucagon-like peptide-1 (GLP-1), and alpha-melanocyte-stimulating hormone (α-MSH) on feeding behavior. T salmon fed consistently across all seasons, whereas NT dramatically reduced their food intake in winter, indicating the seasonal regulation of appetite can be altered by overexpression of GH in T fish. Intraperitoneal injections of CCK-8 and BBS caused a significant and rapid decrease in food intake for both genotypes. Treatment with either GLP-1 or α-MSH resulted in a significant suppression of food intake for NT but had no effect in T coho salmon. The differential response of T and NT fish to α-MSH is consistent with the melanocortin-4 receptor system being a significant pathway by which GH acts to stimulate appetite. Taken together, these results suggest that chronically increased levels of GH alter feeding regulatory pathways to different extents for individual peptides, and that altered feeding behavior in transgenic coho salmon may arise, in part, from changes in sensitivity to peripheral appetite-regulating signals.


Subject(s)
Appetite/physiology , Eating/physiology , Feeding Behavior/physiology , Growth Hormone/genetics , Oncorhynchus kisutch/genetics , Animals , Animals, Genetically Modified , Appetite/drug effects , Bombesin/pharmacology , Cholecystokinin/pharmacology , Eating/drug effects , Feeding Behavior/drug effects , Genotype , Glucagon-Like Peptide 1/pharmacology , Seasons , alpha-MSH/pharmacology
15.
Addict Biol ; 21(4): 802-810, 2016 07.
Article in English | MEDLINE | ID: mdl-25923597

ABSTRACT

We previously showed that paternal cocaine exposure reduced the reinforcing efficacy of cocaine in male offspring. Here, we sought to determine whether paternal cocaine experience could also influence anxiety levels in offspring. Male rats were allowed to self-administer cocaine (controls received saline passively) for 60 days and then were bred with naïve females. Measures of anxiety and cocaine-induced anxiogenic effects were assessed in the adult offspring. Cocaine-sired male offspring exhibited increased anxiety-like behaviors, as measured using the novelty-induced hypophagia and defensive burying tasks, relative to saline-sired males. In contrast, sire cocaine experience had no effect on anxiety-like behaviors in female offspring. When challenged with an anxiogenic (but not anorectic) dose of cocaine (2.5 mg/kg, i.p.), anxiety-like behavior was enhanced in all animals to an equal degree regardless of sire drug experience. Since anxiety and depression are often co-morbid, we also assessed measures of depressive-like behavior. Sire cocaine experience had no effect on depression-like behaviors, as measured by the forced swim task, among male offspring. In a separate group of naïve littermates, select neuronal correlates of anxiety were measured. Male offspring of cocaine-experienced sires showed increased mRNA and protein expression of corticotropin-releasing factor receptor 2 in the hippocampus. Together, these results indicate that cocaine-experienced sires produce male progeny that have increased baseline anxiety, which is unaltered by subsequent cocaine exposure.


Subject(s)
Anxiety/chemically induced , Behavior, Animal/drug effects , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Paternal Exposure/statistics & numerical data , Animals , Cocaine/administration & dosage , Disease Models, Animal , Dopamine Uptake Inhibitors/administration & dosage , Fathers , Female , Male , Pregnancy , Rats , Rats, Sprague-Dawley , Sex Factors
16.
J Clin Child Adolesc Psychol ; 44(3): 446-55, 2015.
Article in English | MEDLINE | ID: mdl-24483145

ABSTRACT

This study examines the role of characterological self-blame as a unique risk factor associated with other known risk factors (depression and its behavioral and social correlates) for continued victimization across the 1st year of middle school. Relying on a large, ethnically diverse sample of 1,698 young adolescents (M(age) = 11.57, SD = .39; 55% female), self-report assessments in the fall and spring included perceptions of victim status, depressive symptoms, friendships, aggression, and responses to a hypothetical victimization vignette assessing both appraisals (characterological self-blame) and behavioral reactions (helpless responding). In addition to depression, characterological self-blame emerged as the most consistent unique risk factor for subsequent victimization. Mediation analysis suggested that the continuity of victimization between fall and spring could be partially explained by increases in characterological self-blame and depressive symptoms. In addition, cross-lagged panel analyses indicated reciprocal relations between peer victimization and characterological self-blame, suggesting cyclical processes. The study findings suggest that attribution retraining in the beginning of middle school might help prevent escalating risk for continued peer victimization.


Subject(s)
Bullying/psychology , Crime Victims/psychology , Depression/psychology , Guilt , Self Concept , Adolescent , Child , Female , Humans , Male , Peer Group , Personality , Risk Factors , Schools , Social Perception
17.
J Neurosci ; 33(36): 14446-54, 2013 Sep 04.
Article in English | MEDLINE | ID: mdl-24005296

ABSTRACT

Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents.


Subject(s)
Cocaine/pharmacology , Deep Brain Stimulation , Drug-Seeking Behavior/physiology , Nucleus Accumbens/physiology , Animals , Drug-Seeking Behavior/drug effects , GABA Agonists/pharmacology , GABAergic Neurons/physiology , Interneurons/physiology , Male , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley
18.
bioRxiv ; 2024 Mar 03.
Article in English | MEDLINE | ID: mdl-38464283

ABSTRACT

Current theories of decision making propose that decisions arise through competition between choice options. Computational models of the decision process estimate how quickly information about choice options is integrated and how much information is needed to trigger a choice. Experiments using this approach typically report data from well-trained participants. As such, we do not know how the decision process evolves as a decision-making task is learned for the first time. To address this gap, we used a behavioral design separating learning the value of choice options from learning to make choices. We trained male rats to respond to single visual stimuli with different reward values. Then, we trained them to make choices between pairs of stimuli. Initially, the rats responded more slowly when presented with choices. However, as they gained experience in making choices, this slowing reduced. Response slowing on choice trials persisted throughout the testing period. We found that it was specifically associated with increased exponential variability when the rats chose the higher value stimulus. Additionally, our analysis using drift diffusion modeling revealed that the rats required less information to make choices over time. Surprisingly, we observed reductions in the decision threshold after just a single session of choice learning. These findings provide new insights into the learning process of decision-making tasks. They suggest that the value of choice options and the ability to make choices are learned separately, and that experience plays a crucial role in improving decision-making performance.

19.
bioRxiv ; 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38562679

ABSTRACT

The frontal cortex plays a critical role in decision-making. One specific frontal area, the anterior cingulate cortex, has been identified as crucial for setting a threshold for how much evidence is needed before a choice is made (Domenech & Dreher, 2010). Threshold is a key concept in drift diffusion models, a popular framework used to understand decision-making processes. Here, we investigated the role of the prelimbic cortex, part of the rodent cingulate cortex, in decision making. Male and female rats learned to choose between stimuli associated with high and low value rewards. Females learned faster, were more selective in their responses, and integrated information about the stimuli more quickly. By contrast, males learned more slowly and showed a decrease in their decision thresholds during choice learning. Inactivating the prelimbic cortex in female and male rats sped up decision making without affecting choice accuracy. Drift diffusion modeling found selective effects of prelimbic cortex inactivation on the decision threshold, which was reduced with increasing doses of the GABA-A agonist muscimol. Stimulating the prelimbic cortex through mu opioid receptors slowed the animals' choice latencies and increased the decision threshold. These findings provide the first causal evidence that the prelimbic cortex directly influences decision processes. Additionally, they suggest possible sex-based differences in early choice learning.

20.
eNeuro ; 11(5)2024 May.
Article in English | MEDLINE | ID: mdl-38724267

ABSTRACT

Current theories of decision-making propose that decisions arise through competition between choice options. Computational models of the decision process estimate how quickly information about choice options is integrated and how much information is needed to trigger a choice. Experiments using this approach typically report data from well-trained participants. As such, we do not know how the decision process evolves as a decision-making task is learned for the first time. To address this gap, we used a behavioral design separating learning the value of choice options from learning to make choices. We trained male rats to respond to single visual stimuli with different reward values. Then, we trained them to make choices between pairs of stimuli. Initially, the rats responded more slowly when presented with choices. However, as they gained experience in making choices, this slowing reduced. Response slowing on choice trials persisted throughout the testing period. We found that it was specifically associated with increased exponential variability when the rats chose the higher value stimulus. Additionally, our analysis using drift diffusion modeling revealed that the rats required less information to make choices over time. These reductions in the decision threshold occurred after just a single session of choice learning. These findings provide new insights into the learning process of decision-making tasks. They suggest that the value of choice options and the ability to make choices are learned separately and that experience plays a crucial role in improving decision-making performance.


Subject(s)
Choice Behavior , Rats, Long-Evans , Reward , Animals , Male , Choice Behavior/physiology , Decision Making/physiology , Rats , Learning/physiology , Reaction Time/physiology , Photic Stimulation/methods , Behavior, Animal/physiology
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