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Biological Psychiatry Jun 2024Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that...
BACKGROUND
Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that cocaine exposure induces plasticity in broad, genetically-defined cell types in the NAc; however, in response to a stimulus, only a small percent of neurons are transcriptionally active - termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure.
METHOD
Using Arc-CreER transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure [either acute (1 x 10mg/kg IP), or repeated (10 x 10mg/kg IP)]. Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with SUD.
RESULTS
Repeated cocaine exposure reduced the size of the ensemble, while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement.
CONCLUSIONS
We show that repeated, but not acute, cocaine exposure induces a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, that is uniquely capable of modulating reinforcement behavior.
PubMed: 38901723
DOI: 10.1016/j.biopsych.2024.06.008 -
Cells Jun 2024Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is...
Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator , a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in , resulted in defective pathogen avoidance behavior against (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in mutants. Calcium imaging in URX neurons showed that mutants displayed longer-lasting calcium transients in response to an O upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior.
Topics: Animals; Caenorhabditis elegans; Lipid Metabolism; Caenorhabditis elegans Proteins; Neurons; Pseudomonas aeruginosa; Calcium; Mutation; Avoidance Learning; Receptors, Cytoplasmic and Nuclear
PubMed: 38891110
DOI: 10.3390/cells13110978 -
Brain and Behavior Jun 2024Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various...
BACKGROUND
Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta (Aβ).
METHODS
Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively.
RESULTS
The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats.
CONCLUSIONS
These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aβ through modulation of oxidative-antioxidant status.
Topics: Animals; Amyloid beta-Peptides; Anxiety; Rats; Male; Selegiline; Memory Disorders; Oxidative Stress; Alzheimer Disease; Disease Models, Animal; Avoidance Learning; Peptide Fragments; Spatial Memory; Maze Learning; Rats, Wistar; Recognition, Psychology; Behavior, Animal; Neuroprotective Agents; Antioxidants
PubMed: 38873869
DOI: 10.1002/brb3.3599 -
Neuron Jun 2024In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior...
In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.
PubMed: 38870929
DOI: 10.1016/j.neuron.2024.05.019 -
Psychiatria Polska Feb 2024The study aimed to validate the Brief Experiential Avoidance Questionnaire (BEAQ) in Polish and establish its psychometric properties.
OBJECTIVES
The study aimed to validate the Brief Experiential Avoidance Questionnaire (BEAQ) in Polish and establish its psychometric properties.
METHODS
A representative sample of the Polish population (N = 1,216) in terms of gender, age, education, and place of residence participated in the online study. The adaptation was conducted with back translation to preserve fidelity to the original version. Apart from BEAQ, participants filled in questionnaires measuring the levels of depression, cognitive fusion, mindfulness and psychological flexibility.
RESULTS
Confirmatory factor analysis showed that the unidimensional model insufficiently fit the data, similarly to other reports on BEAQ validations. Exploratory factor analysis using oblimin rotation extracted two factors labeled "cognitive-emotional avoidance" and "behavioral avoidance" with internal consistency (α) of 0.78 and 0.74, respectively, and stability over time of r = 0.79 and 0.75 in a 21-day test-retest measurement. The subscales demonstrated satisfactory convergent and discriminant validity.
CONCLUSIONS
The Polish BEAQ validation demonstrates it is a tool that can be successfully used in research and clinical practice as it provides a reliable measure of experiential avoidance and is convenient thanks to its limited duration.
Topics: Humans; Female; Male; Poland; Adult; Psychometrics; Surveys and Questionnaires; Reproducibility of Results; Avoidance Learning; Middle Aged; Young Adult
PubMed: 38852185
DOI: 10.12740/PP/162165 -
ENeuro Jun 2024The retrosplenial cortex (RSC) is a hub of diverse afferent and efferent projections thought to be involved in associative learning. RSC shows early pathology in mild...
The Granular Retrosplenial Cortex Is Necessary in Male Rats for Object-Location Associative Learning and Memory, But Not Spatial Working Memory or Visual Discrimination and Reversal, in the Touchscreen Operant Chamber.
The retrosplenial cortex (RSC) is a hub of diverse afferent and efferent projections thought to be involved in associative learning. RSC shows early pathology in mild cognitive impairment and Alzheimer's disease (AD), which impairs associative learning. To understand and develop therapies for diseases such as AD, animal models are essential. Given the importance of human RSC in object-location associative learning and the success of object-location associative paradigms in human studies and in the clinic, it would be of considerable value to establish a translational model of object-location learning for the rodent. For this reason, we sought to test the role of RSC in object-location learning in male rats using the object-location paired-associates learning (PAL) touchscreen task. First, increased cFos immunoreactivity was observed in granular RSC following PAL training when compared with extended pretraining controls. Following this, RSC lesions following PAL acquisition were used to explore the necessity of the RSC in object-location associative learning and memory and two tasks involving only one modality: trial-unique nonmatching-to-location for spatial working memory and pairwise visual discrimination/reversal. RSC lesions impaired both memory for learned paired-associates and learning of new object-location associations but did not affect performance in either the spatial or visual single-modality tasks. These findings provide evidence that RSC is necessary for object-location learning and less so for learning and memory involving the individual modalities therein.
Topics: Animals; Male; Memory, Short-Term; Spatial Memory; Association Learning; Rats, Long-Evans; Visual Perception; Rats; Gyrus Cinguli; Reversal Learning; Conditioning, Operant; Discrimination, Psychological; Cerebral Cortex
PubMed: 38844347
DOI: 10.1523/ENEURO.0120-24.2024 -
PloS One 2024A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning...
A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning experience; this effect has been observed after systemic and local administration of amnestic drugs into several brain areas, including the striatum. However, the effects of amnestic treatments on the process of extinction after intense training have not been studied. Previous research demonstrated increased spinogenesis in the dorsomedial striatum, but not in the dorsolateral striatum after intense training, indicating that the dorsomedial striatum is involved in the protective effect of intense training. To investigate this issue, male Wistar rats, previously trained with low, moderate, or high levels of foot shock, were used to study the effect of tetrodotoxin inactivation of dorsomedial striatum on memory consolidation and subsequent extinction of inhibitory avoidance. Performance of the task was evaluated during seven extinction sessions. Tetrodotoxin produced a marked deficit of memory consolidation of inhibitory avoidance trained with low and moderate intensities of foot shock, but normal consolidation occurred when a relatively high foot shock was used. The protective effect of intense training was long-lasting, as evidenced by the high resistance to extinction exhibited throughout the extinction sessions. We discuss the possibility that increased dendritic spinogenesis in dorsomedial striatum may underly this protective effect, and how this mechanism may be related to the resilient memory typical of post-traumatic stress disorder (PTSD).
Topics: Animals; Male; Rats, Wistar; Extinction, Psychological; Rats; Avoidance Learning; Corpus Striatum; Tetrodotoxin; Memory Consolidation; Amnesia; Electroshock
PubMed: 38843228
DOI: 10.1371/journal.pone.0305066 -
Behavioural Brain Research Jul 2024Safety behaviors are responses that can reduce or even prevent an expected threat. Moreover, empirical studies have shown that using safety behaviors to a learnt safety...
Safety behaviors are responses that can reduce or even prevent an expected threat. Moreover, empirical studies have shown that using safety behaviors to a learnt safety stimulus can induce threat beliefs to it. No research so far has examined whether threat beliefs induced this way generalize to other novel stimuli related to the safety stimulus. Using a fear and avoidance conditioning model, the current study (n=116) examined whether threat beliefs induced by safety behaviors generalize to other novel generalization stimuli (GSs). Participants first acquired safety behaviors to a threat predicting conditioned stimulus (CSthreat). Safety behaviors could then be performed in response to one safe stimulus (CSsafeShift) but not to another (CSsafe). In a following generalization test, participants showed a significant but small increase in threat expectancies to GSs related to CSsafeShift compared to GSs related to CSsafe. Interestingly, the degree of safety behaviors used to the CSsafeShift predicted the subsequent increase in generalized threat expectancies, and this link was elevated in trait anxious individuals. The findings suggest that threat beliefs induced by unnecessary safety behaviors generalize to other related stimuli. This study provides a potential explanation for the root of threat belief acquisition to a wide range of stimuli or situations.
Topics: Humans; Fear; Male; Generalization, Psychological; Female; Young Adult; Conditioning, Classical; Avoidance Learning; Safety; Adult; Anxiety; Adolescent
PubMed: 38825020
DOI: 10.1016/j.bbr.2024.115078 -
BMC Cancer May 2024Death anxiety is thought to cause a range of mental disorders among cancer patients, which may affect their mental health and even quality of life. This study sought to...
BACKGROUND
Death anxiety is thought to cause a range of mental disorders among cancer patients, which may affect their mental health and even quality of life. This study sought to investigate experiential avoidance, meaning in life, and death anxiety among Chinese cancer patients and then explore the relationship between these 3 variables.
METHODS
A total of 300 cancer patients recruited from a tertiary cancer hospital participated in this study from October to December 2021. A cross-sectional survey was conducted using a demographic and clinical characteristics questionnaire, the Acceptance and Action Questionnaire II, the Meaning in Life Questionnaire, and Templer's Death Anxiety Scale. Correlation analysis, hierarchical regression analysis, and mediating effect analysis were used to analyze the relationship among experiential avoidance, meaning in life (including 2 dimensions: presence of meaning and search for meaning), and death anxiety.
RESULTS
A total of 315 questionnaires were distributed, and 300 valid questionnaires were returned, resulting in a valid response rate of 95.2%. Experiential avoidance (r = 0.552, p < 0.01) was moderately positively correlated with death anxiety. Presence of meaning (r = - 0.400, p < 0.01) was moderately negatively correlated with death anxiety, while search for meaning (r = - 0.151, p < 0.01) was weakly negatively correlated with death anxiety. Regression analysis showed that experiential avoidance (β = 0.464) and presence of meaning (β = -0.228) were predictors of death anxiety. Mediating effect analysis revealed that presence of meaning either completely or partially mediated the effect of experiential avoidance and death anxiety, and the indirect effect accounted for 14.52% of the total effect.
CONCLUSION
Overall, experiential avoidance predicts death anxiety in cancer patients, and meaning in life can mediate this effect. The results of this study provide a new path for studying the mechanism of death anxiety and suggest a more positive and promising strategy for its management.
Topics: Humans; Cross-Sectional Studies; Male; Female; Neoplasms; Middle Aged; Anxiety; Attitude to Death; Surveys and Questionnaires; Quality of Life; Adult; Aged; Avoidance Learning; China
PubMed: 38822257
DOI: 10.1186/s12885-024-12433-0 -
Physiological Reports Jun 2024Inflammation and oxidative stress upset memory. We explored influence of sodium nitroprusside (SNP) on memory deficits resulted from lipopolysaccharide (LPS).Groups...
Inflammation and oxidative stress upset memory. We explored influence of sodium nitroprusside (SNP) on memory deficits resulted from lipopolysaccharide (LPS).Groups include control, LPS, LPS + SNP 1 mg/kg, LPS + SNP 2 mg/kg, and LPS + SNP 3 mg/kg. Morris water maze and passive avoidance tests and biochemical measurements were carried out.In Morris water maze, LPS prolonged time and distance for finding the platform. In probe trial, it diminished time spent and traveled distance in the target zone. Injection of 2 and 3 mg/kg of SNP overturned the effect of LPS. In passive avoidance task, LPS postponed entrance into darkroom and reduced time spent in light room and incremented time spent in darkroom in 3, 24, and 72 h after electrical shock. All three doses of SNP restored the effects of LPS. Biochemical experiments confirmed that LPS elevated interleukin-6 and malondialdehyde concentration and declined total thiol content and superoxide dismutase and catalase activity in the hippocampus and cortex tissues. SNP particularly at a 3 mg/kg dose ameliorated LPS effects on these parameters.SNP attenuated memory disabilities resulting from LPS through modifying inflammation and boosting antioxidant defense.
Topics: Animals; Lipopolysaccharides; Nitroprusside; Male; Oxidative Stress; Rats; Memory Disorders; Rats, Wistar; Inflammation; Avoidance Learning; Maze Learning; Hippocampus
PubMed: 38806440
DOI: 10.14814/phy2.16053