Acute early life stress alters threat processing in adult rats
Individuals diagnosed with stress-related psychiatric disorders in adulthood are likely to have experienced early life stress, suggesting that early adversity is an important vulnerability factor in the subsequent development of trauma- and anxiety-related psychiatric illness. It is important to develop animal models of psychiatric dysfunction to determine evident vulnerability considerations, potential biomarkers, and novel treatment avenues to improve the human condition. In our model of acute early life stress (aELS), 15 footshocks are delivered in a single session on postnatal day 17. The following experiments investigated the persistent impacts of our aELS procedure on stress-enhanced fear learning, anxiety-related behaviors, maintenance of fear, and resistance to extinction in adult male and female rats. The findings from these experiments demonstrate that our aELS procedure yields enhanced fear learning and increased anxiety. This enhanced fear is maintained over time, yet it extinguishes normally. Taken together, these results demonstrate that exposure to 15 footshocks during a single session early in life (postnatal day 17) recapitulates a number of important features of trauma- and anxiety-related disorder symptomatology, but not others. Future studies are needed to determine the persistent physiological phenotypes resulting from aELS and the neurobiological mechanisms that mediate these long-term changes. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Methylphenidate differentially affects the social ultrasonic vocalizations of wild-type and prodromal Parkinsonian rats
Prodromal signs of Parkinson's disease (PD), including vocal communication deficits, are poorly understood and do not respond adequately to current pharmacologic treatments. Norepinephrine dysfunction is involved early in PD; thus, drug therapies targeting norepinephrine may be useful as a treatment of prodromal signs. This study used a validated, translational rodent model of prodromal PD, the male -/- rat, which exhibits ultrasonic vocalization (USV) deficits as early as 2 months of age. The purpose of this preclinical study was to investigate a dose-dependent (2.5, 5.0, 7.5, 10 mg/kg) response of methylphenidate on USV parameters with the hypothesis that methylphenidate would increase vocalization output. Because methylphenidate is a psychostimulant with known adverse side effects, we also hypothesized that potential side effects including anxietylike behavior and spontaneous activity would be increased in a dose-dependent manner. To accomplish this, wild-type (WT) and -/- rats were administered a dose of a vehicle (saline) and a methylphenidate dose in a randomized within-subjects design and then assessed for USVs, anxiety behavior (open field), and limb motor (cylinder) activity. The results suggest that methylphenidate does not alter USV emissions in -/- rats; however, methylphenidate increased the total number of vocalizations and duration of frequency-modulated calls in WT rats. Methylphenidate dose dependently influenced spontaneous movements in both WT and -/- rats, as expected, while methylphenidate increased anxiety in -/- rats and not WT rats. This study demonstrates a difference in response to a psychostimulant between -/- rats and WT rats. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Dopamine-mediated behavioral alterations following exposure to a social video in socially isolated mice during the developmental period
Video exposure is known to affect brain function, yet its impact on neurodevelopmental processes remains unclear. This study aimed to investigate whether exposure to a video depicting social behavior induces behavioral and neurological changes in socially isolated mice. On Postnatal Day (PND) 21, male mice were separated from their dams and randomly assigned to three groups: socially grouped mice; socially isolated mice (ISO), where mice were housed without any social stimulation; and social video-exposed mice (SVE), where mice were exposed to a social video played on a tablet from PND21 to PND56 under socially isolated conditions. On PND56, all animals underwent behavioral tests. Compared to the socially grouped mice and ISO group, the SVE group showed an attenuated response to amphetamine treatment. In the social cognition test, the ISO group exhibited decreased affiliative behavior and increased offensive and defensive behavior. However, the SVE group showed a partial improvement in social cognition, including increased affiliative behaviors and decreased defensive behaviors, although no changes in offensive behaviors were observed. Furthermore, the SVE group exhibited elevated levels of tyrosine hydroxylase and dopamine transporter in key social cognition regions-namely the prefrontal cortex, retrosplenial cortex, and hippocampus. This neurochemical shift implies that socially isolated mice can acquire social behaviors through exposure to video-based social interactions. These effects may be related to the compensatory response of the dopamine system, which is implicated in various psychiatric disorders. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Progesterone treatment is not necessary for sexual experience-enhanced paced mating behavior in estradiol benzoate-primed female rats
Sexual behavior in female rats varies depending on sexual history and the combination of ovarian hormones administered to induce receptivity. Experiment 1 tested whether paced mating behavior differed in sexually experienced rats when receptivity was induced with sequential estradiol benzoate (EB) and progesterone (P) or EB-Alone. Rats gained paced mating experience under EB/P (10 μg EB 48 hr + 1 mg P 4-6 hr before mating) and then were primed with EB-Alone (2 μg EB for 6 days). Rats primed with EB-Alone were fully receptive but returned to the male more slowly, spent less time with the male, had longer interintromission intervals, showed fewer proceptive behaviors and more rejection behaviors, and had significantly longer test durations compared to when rats were primed with EB/P. Experiment 2 tested whether sexual experience-induced changes to paced mating behavior occur under both EB/P and EB-Alone hormone priming regimens. Rats received EB/P or EB-Alone prior to four paced mating tests. With sexual experience under either hormone regimen, rats showed shorter contact-return latencies to intromission, shorter interintromission intervals, and more proceptive behaviors. However, relative to EB/P-primed rats, EB-Alone-primed rats exited the male compartment more frequently after mounts and intromissions, spent less time with the male, had longer interintromission intervals, displayed fewer proceptive behaviors and more rejection behaviors, and had longer test durations, indicating lower sexual motivation. Collectively, these data illustrate that experience-enhanced paced mating behavior occurs with either EB/P or EB-Alone priming, but progesterone further facilitates mating behavior. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
A matter of complexity? The role of the dorsal posterior parietal cortex in processing changes in spatial information across time
The posterior parietal cortex (PPC) is an associative neocortical region that integrates multiple streams of information and is implicated in spatial cognition and decision making. In some cases, however, the PPC is not required for these functions. One possibility is that the PPC is recruited when spatial complexity is high. Yet, few studies of PPC function have explicitly manipulated environmental complexity, complexity of spatial changes, or the temporal structure of spatial tasks. To examine whether task complexity recruits PPC function, we tested rats with neurotoxic damage to the dorsal PPC on a series of tasks varying in spatial and temporal complexity. Recognition memory was first assessed in standard exploration tasks, including object recognition, object location, and object in place, as well as a more complex object task in which spatial changes occurred across multiple delays. Spatial navigation was assessed in the circular hole board maze (Barnes maze), and temporal processing was assessed in a temporal order task. PPC damage spared performance on standard recognition memory tasks but caused deficits on tasks involving changes in object configuration or multiple changes across time. PPC damage spared acquisition on the Barnes maze but impaired retention and decreased efficiency of search strategies. PPC damage did not impact temporal order memory. Overall, these results suggest that the PPC is necessary when spatial complexity of the task increases attentional and long-term memory demands. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Taste enhances the ability to express a preference for a congruent odor in rats
Foods that make up a typical diet are characterized by a rich set of sensory qualities that are perceived through multiple different modalities. It is well known that multisensory aspects of food are integrated to create our perception of flavor, which in turn affects our behavioral responses to food. However, the principles underlying multisensory integration of flavor-related sensory signals and how they inform perceptual judgments remain poorly understood, partly due to lack of control over flavor experience in human subjects. Here, we used rats as a model to overcome this limitation and tested the hypothesis that taste can enhance discriminability of retronasal odor cues. In a series of two-bottle tests, animals chose between two odorized solutions after learning to associate one of the odors with saccharin. When odors were highly similar, animals showed little preference for the saccharin-associated odor. When adding saccharin to both bottles-rendering one of the solutions' congruent-animals' preference for the saccharin-associated odor was significantly enhanced. No effect of taste was observed when using dissimilar odor pairs or novel taste stimuli. These findings suggest that congruent taste stimuli selectively enhance odor identity representations, aiding in the discriminability of perceptually similar flavors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Memory reconsolidation and amnesia induction: Separate processes dependent on specific protein and RNA synthesis
The reconsolidation hypothesis posits that memory retrieval initiates a phase of memory destabilization, followed by restabilization through protein synthesis-dependent processes. The disruption of reconsolidation by amnestic agents can lead to memory loss. Yet, this hypothesis leaves unanswered questions regarding the mechanisms driving amnesia induction and reversal of molecular and structural changes underlying memory retention. Our previous work proposed that amnesia induction is an active process reliant on both translation and transcription. To test this hypothesis, we explored the role of N-methyl-D-aspartate (NMDA) glutamate receptors, as well as protein and RNA synthesis in amnesia induction mechanisms in grape snails trained with conditional food aversion, during the initial hours following memory reconsolidation disruption. Our results reveal that protein synthesis inhibitor administration before the conditioned reminder stimulus caused amnesia 3 hr after the reminder, whereas NMDA glutamate receptor antagonists resulted in amnesia less than 20 min following the first conditioned reminder stimulus. Concurrent administration of an NMDA receptor antagonist and a protein synthesis inhibitor before the reminder resulted in a rapid (less than 20 min) and complete prevention of amnesia, underscoring the pivotal role of protein synthesis in NMDA-dependent amnesia induction. Conversely, RNA synthesis inhibitors did not affect memory reconsolidation but inhibited amnesia triggered by an NMDA receptor antagonist. Moreover, our study demonstrates a significant difference in the dependency of memory reconsolidation and amnesia induction "time windows" on protein synthesis. These findings lend support to our hypothesis that memory reconsolidation and amnesia represent distinct processes, each characterized by unique developmental dynamics and molecular underpinnings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Slight and hidden hearing loss in young rats is associated with impaired recognition memory and reduced myelination in the corpus callosum
Slight and hidden hearing loss in children have been linked to cognitive and social difficulties, and yet the neurobiological mechanisms behind these issues remain poorly understood. Most animal models focus on severe hearing loss, leaving the effects of hidden or slight hearing loss largely unexplored. To uncover the neural mechanisms connecting slight/hidden hearing loss to cognitive and social challenges, we induced hearing loss in young (4-week-old) Wistar rats through noise exposure. We then examined cognitive function (object recognition test) and social behavior (juvenile play behavior and social interaction). Changes in brain anatomy were assessed using cortical thickness and hippocampal size measurements, while (immuno)histochemical staining investigated neuronal circuitry maturation (myelin basic protein, parvalbumin, and perineuronal nets) and neurogenesis (doublecortin). Noise-exposed rats displayed slight high-frequency hearing loss (around 20 dB) and hidden hearing loss at other tested frequencies. This slight/hidden hearing loss was associated with impaired object recognition but did not alter social behavior. Slight/hidden hearing loss was associated with reduced myelin basic protein expression in the corpus callosum but no other alterations in cortical thickness, hippocampal size, or other markers of maturation and neurogenesis were found. These findings show that even slight/hidden hearing loss can lead to subtle brain alterations tied to cognitive deficits. This study emphasizes the need for further research to fully understand the brain changes associated with slight/hidden hearing loss and to pinpoint the mechanisms connecting these changes to behavioral deficits. This information is crucial to develop interventions to prevent the cognitive and social consequences of hearing loss. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Effects of repeated social stress on risk assessment behaviors and response to diazepam in the elevated plus maze in adult male rats
Anxiety is highly common, and stress is a major trigger for anxiety. Anxiety includes heightened threat assessment and avoidance, but we do not fully understand which components are sensitive to stress. Rodents show a balance of exploration and avoidance that incorporates threat assessment prior to making the relatively risky decision to explore an open area. The purpose of this study was to determine if stress impacts risk assessment and if this is tied to the effects of stress on exploration. The present study used elevated plus maze (EPM) to test the effects of repeated social defeat stress (RSDS) on risk assessment behaviors in adult male rats. We then tested the effects of diazepam, an anxiolytic that reduces the impact of stress on EPM exploration, to further clarify the relationship between risk assessment and risky behavior in the EPM. We found that RSDS decreased time in the open arm, similar to prior studies. We also found that RSDS increased the likelihood of the primary risk assessment behavior, stretch and attend posture (SAP), increased SAP prior to entering an open arm, and decreased the likelihood that a rat would enter an open arm after SAP. Diazepam ameliorated the effects of RSDS on both SAP and exploratory behavior, further linking risk assessment and subsequent exploratory behaviors. These results suggest that increased risk assessment and reduced risky choices after risk assessment are tied to effects of stress on exploration and provide novel insight into how stress may increase avoidance by effects on risk assessment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Trait-level somatic anxiety modulates functional magnetic resonance imaging (fMRI) neural synchrony to naturalistic stimuli
Somatic anxiety refers to the tendency to appraise situations as threatening, leading to heightened physiological arousal. Symptoms associated with higher levels of somatic anxiety that reflect autonomic arousal and perceptions of threat include elevated heartbeat perception, difficulty breathing, and palpitation. Somatic anxiety is generally associated with increased stimulus-driven attention; however, it is currently unknown how somatic anxiety modulates neural synchrony, measured by intersubject correlations (ISC), in response to complex audiovisual stimuli. The present study seeks to identify how differing levels of somatic anxiety are associated with neural synchrony during psychological processing of audiovisual stimuli, as measured by ISC and intersubject representational similarity analyses. We hypothesize that individuals with higher levels of somatic anxiety will show heightened ISC in response to an audiovisual stimulus in regions associated with stimulus-driven attention, including the superior parietal lobule, supplementary motor area, and precentral gyrus. Results from this study identified that higher levels of somatic anxiety are associated with widespread heightened ISC across the brain, including in regions associated with perceptual processing and stimulus-driven attention. Taken together, this research suggests that higher levels of somatic anxiety are associated with similar processing in brain regions involved in stimulus-driven attention and top-down processing, whereas lower levels of somatic anxiety are associated with similar processing in brain regions associated with higher level visual processing. These results collectively emphasize that somatic anxiety levels should be measured and controlled for during naturalistic functional magnetic resonance imaging paradigms, as this trait may have an influence on synchronous neurological activity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Effects of manipulating prefrontal activity and dopamine D1 receptor signaling in an appetitive feature-negative discrimination learning task
Healthy cognition requires inhibitory modulation of associative learning; conversely, impaired inhibitory discrimination is implicated in behavioral disorders. The medial prefrontal cortex (mPFC) and its dopamine innervation are key to understanding inhibition and impulsivity. We therefore examined the role of prelimbic and infralimbic cortices in within-subjects appetitive feature-negative learning using microinfusions of (a) the gamma-aminobutyric acid-A receptor agonist muscimol (0.25 μg in 1.0 μl; = 35), (b) the dopamine D1 receptor agonist SKF-81297 (0.1 μg in 1.0 μl; = 33), and (c) the dopamine D1 receptor antagonist SCH-23390 (5 μg in 1.0 μl; = 35). A conditioned stimulus (CS) was followed by food, but on trials on which the CS (A+) was compounded with the inhibitory cue (AX-), the food delivery was canceled. Difference scores (CS-preCS responding) were used to measure learning. All three experiments showed the feature-negative discrimination (A+/AX-), as decreased responding to AX- versus A+. This discrimination was reduced but preserved following muscimol infusions in Experiment 1. Similarly, in Experiments 2 and 3, infusions of SKF-81297 and SCH-23390 were both without effect on the acquisition of the discrimination. Like muscimol, SCH-23390 reduced difference score responding, consistent with nonspecific effects on the (expression of) learning. Thus, there was no evidence to suggest that inactivation of prelimbic or infralimbic cortices impaired feature-negative discrimination learning and no evidence for dopaminergic modulation of such learning in the medial prefrontal cortex either. These results are discussed in the context of the nonspecific effects of the infusions and the overall inconsistent performance in summation and retardation tests of conditioned inhibition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Chronic stressor exposure impairs extinction of fear in adolescent rats and has associated effects on perineuronal nets and parvalbumin interneurons
Adolescents, both human and nonhuman, exhibit impairments in the extinction of learned fear, an effect that is exacerbated, at least in rodents, by exposure to chronic stress. However, we have little understanding of the mechanisms underlying this effect. Therefore, here, we examined whether corticosterone exposure, a model of chronic stress, alters the expression of inhibitory neurons expressing parvalbumin (PV) in the basolateral amygdala and prefrontal cortex, two brain regions that have been implicated in fear extinction memories, in adolescent rats. We also examined the expression of perineuronal nets (PNNs), extracellular matrix structures that encompass inhibitory interneurons, in these two regions. These structures might render fear memories resistant to extinction by applying a structural "brake" on the plasticity of fear memories. Corticosterone-exposed adolescent rats exhibited poor extinction retention, as in past work, and were also found to have reduced percentage of PV-positive cells surrounded by PNNs in the basolateral amygdala. PV cells and PNNs were unaffected by corticosterone exposure in the prefrontal cortex. Our results suggest that the altered function of amygdala interneurons may be associated with the impaired extinction performance in stress-exposed adolescent rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Impact of supplementation with omega-3 fatty acids after maternal dietary deficiency on adolescent anxiety and microglial morphology
Dietary maternal deficiency in omega-3 polyunsaturated fatty acids (n-3 PUFA) is a potential risk factor for the development of anxiety and other mood disorders in children and adolescents. Here, we used a previously characterized maternal PUFA dietary deficiency model in rats to determine the impact of postweaning supplementation on adolescent anxiety-like behaviors. We focused on two models of anxiety: innate anxiety tested by the elevated plus maze and a novel operant model of learned anxiety where animals learn that actions may be associated with a variable probability of harm. Given that recent basic and clinical studies have associated anxiety and other adverse effects of PUFA deficiency on inflammatory processes and microglial structure and function, we also assessed the impact of our dietary deficiency model and supplementation on adolescent microglial morphology in multiple brain regions. We found that the male and female adolescent PUFA-deficient groups exhibit increased innate anxiety, but only females showed enhanced learned anxiety. Supplementation after weaning did not significantly affect innate anxiety but ameliorated learned anxiety in females. Thus, the beneficial effects of supplementation on adolescent anxiety may be sex-specific and depend on the type of anxiety. We also found that PUFA deficiency influences microglia function in adolescents in the amygdala and nigrostriatal, but not mesolimbic, brain regions. Collectively, these data suggest that while PUFA dietary supplementation may be effective in reducing adolescent anxiety, this effect is context-, sex-, and brain network-specific. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Electrophysiological and hemodynamic mechanisms underlying load modulations in visuospatial working memory: A functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) study
The n-back task has been widely used to study working memory. Previous studies investigating the electrophysiological (electroencephalogram [EEG]) and hemodynamic correlates (functional near-infrared spectroscopy [fNIRS]) of the n-back task have been generally based on verbal stimuli and only investigated EEG frequency bands. We simultaneously acquired the EEG and fNIRS in 35 participants (16 males; age = 26.4 ± 4.3 years; educational attainment = 18 ± 2 years) during a visuospatial n-back task. The task encompassed a control condition and a low (requiring to recall one previous stimulus) and a high (requiring to recall two previous stimuli) working memory load experimental conditions. Accuracy decreased and reaction times slowed in the high compared to both low load and control conditions. Regarding EEG, P3a showed higher amplitude in the experimental conditions compared to the control one, and P3b exhibited higher amplitude in the low compared to the high load condition. Regarding fNIRS, the high load condition showed higher deoxygenated hemoglobin compared to the control one. Moreover, the central frontopolar cortex showed higher activation compared with the left frontal cortex. Our study showed that working memory load during a visuospatial n-back task influenced behavioral and electrophysiological indices. Even if the load effect was only observed for deoxygenated hemoglobin on hemodynamic data, this was in line with previous studies and coherent with its electrophysiological correlates. Thus, our study confirms that EEG and fNIRS can be successfully used in multimodal acquisitions, but also highlights that future studies are needed to develop a novel version of the task. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Translational approaches to the neurobiological study of conditional discrimination and inhibition: Implications for psychiatric disease
There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses. The objective of this review is to give an overview of the conditional discrimination and inhibition findings reported in both animal models and human neuropsychiatric disorders. Both behavioral and neural findings are reviewed among human and rodent studies that include conditional fear discrimination via conditional stimuli with and without reinforcement (CS+ vs. CS-, respectively) and/or conditional inhibition of fear through assessment of the fear response to a compound CS-/CS+ cue versus CS+. There are several parallels across species in behavioral fear expression as well as neural circuits promoting fear reduction in response to a CS- and/or CS-/CS+ compound cue. Continued and increased efforts to compare similar behavioral fear inhibition paradigms across species are needed to make breakthrough advances in our understanding and treatment approaches to individuals with fear disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Beyond reconsolidation: The need for a broad theoretical approach in clinical translations of research on retrieval-induced plasticity
Experimental findings showing that retrieved memories are labile and vulnerable to disruption have led to important theoretical ideas at a basic science level that have been applied to the clinic at a translational level. At a theoretical level, these findings suggest that retrieved memories can be modulated by behavioral or pharmacological treatments as they are reconsolidated and returned to storage. At a clinical level, these findings suggest that treatments that target reconsolidation may help dampen or even erase especially problematic memories, such as those associated with trauma. However, there are many caveats to these effects and issues that need to be considered when thinking broadly about retrieval-induced plasticity and extensions into the clinic. First, performance during a memory test often does not reflect the entirety of the animal's knowledge about a situation; asking questions in different ways may reveal the presence of a memory that was thought to be eliminated. Second, although reconsolidation and extinction are often treated as competing processes, there is abundant evidence that extinction can progress through associative and nonassociative changes in the original memory that are often described in terms of reconsolidation effects. Third, targeting a reconsolidation process as a therapeutic may not be helpful in disorders like posttraumatic stress disorder, in which traumatic experiences induce a cascade of symptoms that are self-perpetuating and may ultimately maintain themselves long after trauma. Underlying all of these challenges is the need for a rich theoretical framework focused on retrieval-induced plasticity that is informed by developments in associative learning theory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
A psychological mechanism for the development of anxiety
Although numerous behavioral constructs have been proposed to account for anxiety disorders, how these disorders develop within an individual has been difficult to predict. In this perspective, I selectively review clinical and experimental evidence suggesting that avoidance (i.e., safety) behavior increases beliefs of threat or fear. The experimental evidence has been replicated numerous times, with different parameters, and shows that when human participants emit avoidance responses in the presence of a neutral stimulus, they later show heightened expectations of threat in the presence of the neutral stimulus. I interpret these findings as resulting from prediction errors as anticipated by the Rescorla-Wagner model, although other animal learning theories can also predict the phenomenon. I discuss some implications and offer a few novel predictions. The analysis presented here sheds light on a phenomenon of theoretical and clinical relevance which is accommodated by basic associative learning theory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Modeling impaired insight after drug use in rodents
Impaired insight in substance use disorder has been argued to reflect a global deficit in using cognitive models to mentally simulate possible future outcomes. The process of mentally simulating outcomes allows us to understand our beliefs about their causes, that is, to have insight and thereby avoid potentially negative outcomes. However, work in humans cannot address whether impaired insight and its neural/neurochemical sequalae are present prior to the development of a substance use disorder, a consequence of substance use, or a combination of both. This is because baseline measurements prior to drug use are not possible in humans. However, if these changes can be directly caused by drug use, then in animal models, a history of drug use should cause impairments in behavioral tasks designed to assess such inferences. Focusing on cocaine use, here we will review several lines of research from our laboratory that have tested this question using learning-theory tasks designed to isolate insight. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Fear attenuation collaborations to optimize translation
Here, we describe the efforts we dedicated to the challenge of modifying entrenched emotionally laden memories. In recent years, through a number of collaborations and using a combination of behavioral, molecular, and computational approaches, we: (a) developed novel approaches to fear attenuation that engage mechanisms that differ from those engaged during extinction (Monfils), (b) examined whether our approaches can generalize to other reinforcers (Lee, Gonzales, Chaudhri, Cofresi, and Monfils), (c) derived principled explanations for the differential outcomes of our approaches (Niv, Gershman, Song, and Monfils), (d) developed better assessment metrics to evaluate outcome success (Shumake and Monfils), (e) identified biomarkers that can explain significant variance in our outcomes of interest (Shumake and Monfils), and (f) developed better basic research assays and translated efforts to the clinic (Smits, Telch, Otto, Shumake, and Monfils). We briefly highlight each of these milestones and conclude with final remarks and extracted principles. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
The role of midbrain dopamine cells projecting to the insular cortex in mediated performance: Implications for animal models of reality testing
A growing body of literature indicates that mediated learning techniques have specific utility for tapping into reality testing in animal models of neuropsychiatric illness. In particular, recent work has shown that animal models that recapitulate various endophenotypes of schizophrenia are particularly vulnerable to impairments in reality testing when undergoing mediated learning. Multiple studies have indicated that these effects are dopamine receptor 2-dependent and correlated with aberrant insular cortex (IC) activity. However, until now, the connection between dopamine and the IC had not been investigated. Here, we utilized a novel intersectional approach to label mesencephalic dopamine cells that specifically project to the insular cortex in both wild-type controls and transgenic mice expressing the dominant-negative form of the Disrupted-in-Schizophrenia-1 (DISC-1) gene. Using these techniques, we identified a population of cells that project from the ventral tegmental area (VTA) to the IC. Afterward, we conducted multiple studies to test the necessity of this circuit in behaviors ranging from gustatory detection to the maintenance of effort and, finally, mediated performance. Our results indicate that perturbations of the DISC-1 genetic locus lead to a reduction in the number of cells in the VTA → IC circuit. Behaviorally, VTA → IC circuitry does not influence gustatory detection or motivation to acquire sucrose reward; however, inactivation of this circuit differentially suppresses Pavlovian approach behavior in wild-type and DISC-1 transgenic mice during mediated performance testing. Moreover, under these testing conditions, inactivation of this circuit predisposes wild-type (but not DISC-1) mice to display impaired reality testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Prediction, perception, and psychosis: Application of associative learning theories to schizophrenia research
In recent years, there have been significant advances in our understanding of the positive symptoms of schizophrenia, such as hallucinations and delusions. This progress has been significantly aided by the use of associative learning-based approaches in human subjects and preclinical animal models. Here, we first review experimental research focusing on the abnormal processing of absent stimuli using three different conditioning phenomena: conditioned hallucinations, mediated conditioning, and trace conditioning. We then review studies investigating the ability to reduce focal processing of physically present but informationally redundant stimuli using habituation, latent inhibition, and blocking. The results of these different lines of research are then summarized within the framework of Wagner's (1981) standard operating procedures model, an associative learning model with explicit reference to the internal representations of both present and absent stimuli. Within this framework, the central deficit associated with positive symptoms can be described as a failure to suppress the focal processing of both absent stimuli and present but irrelevant stimuli. This can explain the wide range of results obtained in different experimental settings. Finally, we briefly discuss the role of the hippocampus and its interaction with dopaminergic transmission in the emergence of such abnormal stimulus representations and learning. Overall, we hope that the theoretical framework and empirical findings offered by the associative learning approach will continue to facilitate and integrate analyses of schizophrenia conducted at the psychological and behavioral levels on the one hand, and at the neural and molecular levels on the other, by serving as a useful interface between them. (PsycInfo Database Record (c) 2024 APA, all rights reserved).