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Background: Many military service members are victims of repetitive blast traumatic brain injuries (rbTBI) and endure diverse altered psychological and behavioural conditions during their lifetime. Some of these conditions include anxiety, post-traumatic stress and pain. Thus, this study attempts to fill the knowledge gap on enduring behavioural and neuroinflammatory marker alterations 1 month after rbTBI., Purpose: Although previous rbTBI animal studies have shown behavioural and histopathological changes either a few days (acute) or many months (chronic) after trauma, knowledge related to post-traumatic changes during the intermediate timeframe, i.e. a month after rbTBI is less clear or unavailable., Methods: Sprague-Dawley rats (male; n = 12) were assigned to either rbTBI or sham conditions. Animals assigned to the rbTBI group were subjected to 1 blast exposure per day for three consecutive days, while animals in the sham group were exposed to identical experimental conditions sans blast exposure. All animals were tested for anxiety at baseline. 30 days post-injury, animals were tested again for anxiety and paw thermal sensitivity, followed by brain harvest for immunohistochemical analyses., Results: Animals exposed to rbTBI showed signs of anxiety-like behaviour on parameters of elevated plus-maze and behavioural signs of pain indicated by reduced thermal withdrawal latency of the forepaw. Histologically, brain sections from animals exposed to rbTBI showed a significantly increased number of microglial/macrophage and astrocytic counts in the medial prefrontal cortex., Conclusion: Data from this initial preclinical study support the prevalence of putative anxiety-like behaviour, enhancement in forepaw thermal sensitivity and increase in the number of glial cells even 1 month after rbTBI. These findings have potential implications in the treatment evaluation of blast-exposed military and civilian populations and emphasise the need for devising protective measures for people susceptible to single or repeated exposures. A greater further understanding of rbTBI-related chronic concurrent behavioural and neuropathological sequela is warranted., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Aims: Relapse is a common characteristic of compulsive behaviors like addiction, where individuals tend to return to drug use or overeating after a period of abstinence. PFC (prefrontal cortex) neuronal ensembles are required for drug and food-seeking behaviors and are partially regulated by Norepinephrine (NE). However, the contributions of neuromodulators, such as the adrenergic system, in food-seeking behavior are not fully understood., Main Methods: To investigate this, we trained male and female rats to press a lever in an operant chamber to obtain banana-flavored food pellets for ten days. We then administered DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride), a neurotoxin that diminishes norepinephrine levels in the brain. The rats were kept in their home cages for ten more days before being returned to the operant chambers to measure food-seeking behavior., Key Findings: Despite receiving DSP-4, the PFC neuronal ensembles measured by Fos and food-seeking behavior did not differ between groups, but rather sex., Significance: Although both NE and Fos expressing neurons are implicated in food-seeking, they do not seem to be involved in a cue-contextual induced re-exposure response., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. The animal portion of this manuscript was approved under protocol #. A220814., (© 2024 The Authors.)

First theorized by Hebb, neuronal ensembles have provided a framework for understanding how the mammalian brain operates, especially regarding learning and memory. Neuronal ensembles are discrete, sparsely distributed groups of neurons that become activated in response to a specific stimulus and are thought to provide an internal representation of the world. Beyond the study of region-wide or projection-wide activation, the study of ensembles offers increased specificity and resolution to identify and target specific memories or associations. Neuroscientists interested in the neurobiology of learning, memory, and motivated behavior have used electrophysiological-, calcium-, and protein-based proxies of neuronal activity in preclinical models to better understand the neurobiology of learned and motivated behaviors. Although these three approaches may be used to pursue the same general goal of studying neuronal ensembles, technical differences lead to inconsistencies in the output and interpretation of data. This mini-review highlights some of the methodologies used in electrophysiological-, calcium-, and protein-based studies of neuronal ensembles and discusses their strengths and weaknesses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Davidson, Mascarin, Yahya, Rubio and Gheidi.)

Rationale: The contribution of norepinephrine on the different phases of spatial memory processing remains incompletely understood. To address this gap, this study depleted norepinephrine in the brain and then conducted a spatial learning task with multiple phases., Methods: Male and female Wistar rats were administered 50 mg/kg/i.p. of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) to deplete norepinephrine. After 10 days, rats were trained on a 20-hole Barnes maze spatial navigation task for 5 days. On the fifth day, animals were euthanized and HPLC was used to confirm depletion of norepinephrine in select brain regions. In Experiment 2, rats underwent a similar Barnes maze procedure that continued beyond day 5 to investigate memory retrieval and updating via a single probe trial and two reversal learning periods., Results: Rats did not differ in Barnes maze acquisition between DSP-4 and saline-injected rats; however, initial acquisition differed between the sexes. HPLC analysis confirmed selective depletion of norepinephrine in dorsal hippocampus and cingulate cortex without impact to other monoamines. When retrieval was tested through a probe trial, DSP-4-improved memory retrieval in males but impaired it in females. Cognitive flexibility was transiently impacted by DSP-4 in males only., Conclusions: Despite significantly reducing levels of norepinephrine, DSP-4 had only a modest impact on spatial learning and behavioral flexibility. Memory retrieval and early reversal learning were most affected and in a sex-specific manner. These data suggest that norepinephrine has sex-specific neuromodulatory effects on memory retrieval with a lesser effect on cognitive flexibility and no impact on acquisition of learned behavior., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Acetylcholinergic antagonists have shown some promise in reducing addiction-related behaviors in both preclinical and clinical studies. However, the psychological mechanisms by which these drugs are able to affect addictive behavior remain unclear. A particular key process for the development of addiction is the attribution of incentive salience to reward-related cues, which can be specifically measured in animals using a Pavlovian conditioned approach procedure. When confronted with a lever that predicts food delivery, some rats engage with the lever directly (i.e., they sign track), indicating attribution of incentive-motivational properties to the lever itself. In contrast, others treat the lever as a predictive cue and approach the location of impending food delivery (i.e., they goal track), without treating the lever itself as a reward., Objectives: We tested whether systemic antagonism of the either nicotinic or muscarinic acetylcholine receptors would selectively affect sign- or goal-tracking behavior, indicating a selective effect on incentive salience attribution., Methods: A total of 98 male Sprague Dawley rats were either given the muscarinic antagonist scopolamine (100, 50, or 10 µg/kg i.p.) or the nicotinic antagonist mecamylamine (0.3, 1.0, or 3 mg/kg i.p.) before being trained on a Pavlovian conditioned approach procedure., Results: Scopolamine dose-dependently decreased sign tracking behavior and increased goal-tracking behavior. Mecamylamine reduced sign-tracking but did not affect goal-tracking behavior., Conclusions: Antagonism of either muscarinic or nicotinic acetylcholine receptors can reduce incentive sign-tracking behavior in male rats. This effect appears to be specifically due to a reduction in incentive salience attribution since goal-tracking either increased or was not affected by these manipulations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cue-based associative learning (i.e., Pavlovian conditioning) is a foundational component of behavior in almost all forms of animal life and may provide insight into individual differences in addiction liability. Cues can take on incentive-motivational properties (i.e., incentive salience) through Pavlovian learning. Extensive testing with non-human animals (primarily rats) has demonstrated significant variation among individuals in the behaviors this type of learning evokes. So-named "sign-trackers" and "goal-trackers" have been examined in many studies of non-human animals, but this work in humans is still a nascent area of research. In the present proof-of-concept study, we used a Pavlovian conditioned approach task to investigate human sign- and goal-tracking in emerging adults. Conditioned behaviors that developed over the course of the task were directed toward the reward-cue and toward the reward location. Participants' eye-gaze and behavior during the task were submitted to a latent profile analysis, which revealed three groups defined as sign-trackers (n = 10), goal-trackers (n = 4), and intermediate responders (n = 36). Impulsivity was a significant predictor of the sign-tracking group relative to the goal-tracking group. The present study provides preliminary evidence that a simple procedure can produce learned Pavlovian conditioned approach behavior in humans. Though further investigation is required, findings provide a promising step toward the long-term goal of translating important insights gleaned from basic research into treatment strategies that can be applied to clinical populations., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of ( R,S )-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.

Aging is typically accompanied by both memory decline and changes in hippocampal function. Lasting memory is thought to also require recapitulation of recent memory traces during subsequent rest-a phenomenon termed memory trace reactivation or replay. Replay becomes less synchronized in the CA1 region of aged animals, and while subtle, this deficit may have profound physiological consequences for driving plasticity. Importantly, spike timing changes during replay may impair the induction of plasticity-regulating gene products, such as activity-regulated cytoskeletal protein (Arc). To test this hypothesis, Arc transcription was assessed both during spatial exploration and subsequent memory-related replay in hippocampal CA1 of young and aged animals. A significant age-related difference was observed in the pattern of pyramidal cells expressing Arc during rest, supporting the hypothesis that altered plasticity-related cascade is a major consequence of the changes in coordinated activity that occur during consolidation in older animals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: Pavlovian conditioned approach paradigms are used to characterize the nature of motivational behaviors in response to stimuli as either directed toward the cue (i.e., sign-tracking) or the site of reward delivery (i.e., goal-tracking). Recent evidence has shown that activity of the endocannabinoid system increases dopaminergic activity in the mesocorticolimbic system, and other studies have shown that sign-tracking behaviors are dependent on dopamine., Objectives: Therefore, we hypothesized that administration of a cannabinoid agonist would increase sign-tracking and decrease goal-tracking behaviors., Methods: Forty-seven adult male Sprague-Dawley rats were given a low, medium, or high dose of the cannabinoid agonist CP-55,940 (N = 12 per group) or saline (N = 11) before Pavlovian conditioned approach training. A separate group of rats (N = 32) were sacrificed after PCA training for measurement of cannabinoid receptor type 1 (CB1) and fatty acid amide hydrolase (FAAH) using in situ hybridization., Results: Contrary to our initial hypothesis, CP-55,940 dose-dependently decreased sign-tracking and increased goal-tracking behavior. CB1 expression was higher in sign-trackers compared with that in goal-trackers in the prelimbic cortex, but there were no significant differences in CB1 or FAAH expression in the infralimbic cortex, dorsal or ventral CA1, dorsal or ventral CA3, dorsal or ventral dentate gyrus, or amygdala., Conclusions: These results demonstrate that cannabinoid signaling can specifically influence behavioral biases toward sign- or goal-tracking. Pre-existing differences in CB1 expression patterns, particularly in the prelimbic cortex, could contribute to individual differences in the tendency to attribute incentive salience to reward cues.

Introduction: Chronic administration of cocaine causes a disinhibited, hyperexploratory response to novel environments. As the norepinephrine (NE) system regulates exploration and is dysregulated following cocaine exposure, we hypothesized that this cocaine-mediated hyperexploratory response is associated with increased locus coeruleus (LC) reactivity., Methods: To test this hypothesis, we used dual fluorescent in situ hybridization immunofluorescence to analyze novelty-induced c-fos and tyrosine hydroxylase expression in the LC and high-pressure liquid chromatography to measure dopamine (DA) and NE concentrations in key catecholamine projection regions following exposure to cocaine., Results: Repeated cocaine exposure followed by a 14-day drug-free period increased exploration of novel environments, replicating previous findings. Novelty exposure increased LC c-fos expression, increased anterior cingulate NE, and decreased ventral tegmental area DA. Cocaine exposure decreased amygdala (AMY) DA, but had no effect on LC c-fos expression or NE in any tested brain region. No interactions between cocaine and novelty were found. Open arm exploration was positively correlated with LC c-fos expression and NE concentrations in both the anterior cingulate and nucleus accumbens, and negatively correlated with AMY DA concentration., Conclusions: Our findings confirm that exposure to novel environments increases LC activity and NE in the anterior cingulate cortex, that long-term exposure to cocaine dysregulates AMY DA, and that disinhibited exploration in novel environments correlates with NE and DA in regions that modulate risk-taking and avoidance behavior. Further studies investigating the effects of cocaine on brain catecholamine systems are important in understanding the long-lasting effects of cocaine on brain function., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Arc ensembles in adult rat olfactory bulb (OB) and anterior piriform cortex (PC) were assessed after discrimination training on highly similar odor pairs. Nonselective α- and β-adrenergic antagonists or saline were infused in the OB or anterior PC during training. OB adrenergic blockade slowed, but did not prevent, odor discrimination learning. After criterion performance, Arc ensembles in anterior piriform showed enhanced stability for the rewarded odor and pattern separation for the discriminated odors as described previously. Anterior piriform adrenergic blockade prevented acquisition of similar odor discrimination and of OB ensemble changes, even with extended overtraining. Mitral and granule cell Arc ensembles in OB showed enhanced stability for rewarded odor only in the saline group. Pattern separation was not seen in the OB. Similar odor discrimination co-occurs with increased stability in rewarded odor representations and pattern separation to reduce encoding overlap. The difficulty of similar discriminations may relate to the necessity to both strengthen rewarded representations and weaken overlap across similar representations., Significance Statement: We show for the first time that adrenoceptors in anterior piriform cortex (aPC) must be engaged for adult rats to learn to discriminate highly similar odors. Loss of adrenergic activation in olfactory bulb (OB) slows, but does not prevent, discrimination learning. Both increased stability of the rewarded odor representation and increased pattern separation of the rewarded and unrewarded odors in aPC accompany successful discrimination. In the OB, rewarded odors increase in ensemble stability, but there is no evidence of pattern separation. We suggest that the slow acquisition of similar odor discriminations is related to the differing plasticity requirements for increased stability and pattern separation., (Copyright © 2015 the authors 0270-6474/15/3514070-06$15.00/0.)

Classic models of the hippocampus uniformly ascribe pattern completion to CA3, but recent data suggest CA3c (enclosed by the dentate gyrus) may act in a manner more consistent with the dentate and aid in pattern separation. The ideal test for functional distinction within CA3, however, is to compare the responses in these regions in the same animal in multiple contexts. To accomplish this, animals visited two contexts with varying degrees of similarity and the pattern of repeated Arc expression was examined across the pyramidal cell layer. Under conditions of partial cue change, responses in CA3c are far more distinct than CA3a/b, consistent with evidence for functional diversity along the transverse axis of CA3. These data add to the mounting evidence that "classic" roles ascribed to CA3 in learning and memory require re-evaluation., (© 2014 Wiley Periodicals, Inc.)

The nature of memory is a central issue in neuroscience. How does our representation of the world change with learning and experience? Here we use the transcription of Arc mRNA, which permits probing the neural representations of temporally separated events, to address this in a well characterized odor learning model. Rat pups readily associate odor with maternal care. In pups, the lateralized olfactory networks are independent, permitting separate training and within-subject control. We use multiday training to create an enduring memory of peppermint odor. Training stabilized rewarded, but not nonrewarded, odor representations in both mitral cells and associated granule cells of the olfactory bulb and in the pyramidal cells of the anterior piriform cortex. An enlarged core of stable, likely highly active neurons represent rewarded odor at both stages of the olfactory network. Odor representations in anterior piriform cortex were sparser than typical in adult rat and did not enlarge with learning. This sparser representation of odor is congruent with the maturation of lateral olfactory tract input in rat pups. Cortical representations elsewhere have been shown to be highly variable in electrophysiological experiments, suggesting brains operate normally using dynamic and network-modulated representations. The olfactory cortical representations here are consistent with the generalized associative model of sparse variable cortical representation, as normal responses to repeated odors were highly variable (∼70% of the cells change as indexed by Arc). Learning and memory modified rewarded odor ensembles to increase stability in a core representational component., (Copyright © 2014 the authors 0270-6474/14/3415394-08$15.00/0.)

Background: Aging is typically accompanied by memory decline and changes in hippocampal function. Among these changes is a decline in the activity of the dentate gyrus (DG) during behavior. Lasting memory, however, is thought to also require recapitulation of recent memory traces during subsequent rest - a phenomenon, termed memory trace reactivation, which is compromised in hippocampal CA1 with progressive age. This process has yet to be assessed in the aged DG, despite its prominent role in age-related memory impairment. Using zif268 transcription to measure granule cell recruitment, DG activity in adult and aged animals was assessed both during spatial exploration and as animals remained at rest in the home cage in order to detect potential memory-related replay., Results: Consistent with the observation of memory trace reactivation in DG, the probability that an individual granule cell transcribes zif268 during rest in the animal's home cage is increased by recent experience in a novel environment. Surprisingly, a comparable increase was observed in the probability of granule cells in the aged DG expressing zif268 during rest. Moreover, no significant age-related difference was observed in the number of granule cells expressing zif268 during rest. Thus, the number and pattern of granule cell expression of zif268 during rest is preserved in aged animals, despite a significant decline in exploration-related zif268 expression., Conclusions: These data lead to the hypothesis that the input the aged DG receives from backprojections from CA3 (the region widely hypothesized to mediate reactivation) remains functionally intact despite loss of innervation from the perforant path.

The patterns of ensemble activity in the hippocampal formation during wakeful, attentive behavior are recapitulated during subsequent resting states. This replay of activity has also been found in several brain regions across many species, indicating a very general biological phenomenon. Concomitantly, transcription of immediate-early genes (IEGs) such as Arc also reoccurs in the same hippocampal neurons, suggesting that IEGs contribute to "off-line" consolidation. If continued IEG expression during rest reflects a correlate of ensemble replay, then the same generality should be observed in IEG transcription patterns. This hypothesis was tested by examining Arc in F344 rats engaging in spatial exploration alongside a rest episode. The probability that an individual neuron participates in "constitutive" Arc expression during rest is increased by recent experience in multiple cortical regions as well as across the septal and temporal poles of the hippocampus, consistent with memory trace reactivation. That is, neurons that were recently active during spatial exploration are preferentially recruited into further Arc expression during subsequent rest. The continued Arc expression, however, occurs in only a small fraction of the cells that were engaged in transcription during previous behavior. This fraction is greatest in CA3 and progressively decreases in CA1, superficial, and deep cortical layers and is consistent with the idea that consolidation occurs rapidly in the hippocampus (centering on the CA3 recurrent network) while changes are much more gradual in neocortical synaptic networks., (Copyright © 2012 Wiley Periodicals, Inc.)

Background and Objective: Pulmonary function tests play an important role in the management of pulmonary diseases. One of the tests that are widely used is spirometry. Performing an acceptable spirometry manoeuvre according to the standards set by the American Thoracic Society/European Respiratory Society is difficult. The aim of this study was to compare forced expiratory volume in 3 s (FEV(3)) and forced expiratory volume in 6 s (FEV(6)) with forced vital capacity (FVC), and forced expiratory volume in 1 s FEV(1)/FEV(3) and FEV(1)/FEV(6) with FEV(1)/FVC, in order to substitute the usual spirometric manoeuvres with manoeuvres that are easier to perform., Methods: In a cross-sectional study, spirometry was performed for 588 subjects who were referred for occupational health evaluations. The accuracy of FEV(3), FEV(6), FEV(1)/FEV(3) and FEV(1)/FEV(6) was compared with that of FVC and FEV(1)/FVC. Chi-square tests and kappa tests were used to analyse the data., Results: Individuals with normal (n = 297) and abnormal spirometry (n = 291) were evaluated. The sensitivity, specificity, positive predictive value and negative predictive value of FEV(1) /FEV(6) , as compared with that of FEV(1)/FVC for detecting obstruction, were 93.56, 99.32, 98.95 and 96.09, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of FEV(6), as compared with that of FVC for detecting restriction, were 96.68, 98.65, 96.68 and 98.65, respectively., Conclusions: FEV(6) and FEV(1)/FEV(6) can be used as surrogates for FVC and FEV(1)/FVC, respectively, and these parameters showed acceptable sensitivity, specificity, positive predictive value and negative predictive value for occupational health evaluations., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

It is well known that antidepressants both improve mood and increase the rate at which the dentate gyrus (DG) generates new neurons. In addition to the implications of neurogenesis for mood regulation, the production and survival of granule cells has also been implicated in learning and memory. Despite this evidence, the results of studies on the effect of antidepressants on memory have been mixed. A critical piece of data that may be missing from previous studies, however, is insight into (a) the location that newborn neurons migrate to following fluoxetine administration and (b) their ability to express normal patterns of activity-related genes. Here we demonstrate a finding that may resolve the discrepancy in the effects fluoxetine-induced neurogenesis on mood and memory: after 5 weeks delay, the net additional neurons generated in animals given the antidepressant fluoxetine during treatment are functionally normal, but preferentially accumulate (due to changes in migration and/or survival) in an area of the DG that is not recruited by spatial memory tasks., (Copyright © 2011 Elsevier Ltd. All rights reserved.)