Dataset of active avoidance in Wistar-Kyoto and Sprague Dawley rats: Experimental data and reinforcement learning model code and output.

Data were collected from 40 Wistar-Kyoto (WKY) and 40 Sprague Dawley (SD) rats during an active escape-avoidance experiment. Footshock could be avoided by pressing a lever during a danger period prior to onset of shock. If avoidance did not occur, a series of footshocks was administered, and the rat could press a lever to escape (terminate shocks). For each animal, data were simplified to the presence or absence of lever press and stimuli in each 12-second time frame. Using the pre-processed dataset, a reinforcement learning (RL) model, based on an actor-critic architecture, was utilized to estimate several different model parameters that best characterized each rat's behaviour during the experiment. Once individual model parameters were determined for all 80 rats, behavioural recovery simulations were run using the RL model with each animal's "best-fit" parameters; the simulated behaviour generated avoidance data (percent of trials avoided during a given experimental session) that could be compared across simulated rats, as is customarily done with empirical data. The datasets representing both the experimental data and the model-generated data can be interpreted in various ways to gain further insight into rat behaviour during avoidance and escape learning. Furthermore, the estimated parameters for each individual rat can be compared across groups. Thus, possible between-strain differences in model parameters can be detected, which might provide insights into strain differences in learning. The software implementing the RL model can also be applied to or serve as a template for other experiments involving acquisition learning. Reference for Co-Submission: K.M. Spiegler, J. Palmieri, K.C.H. Pang, C.E. Myers, A reinforcement-learning model of active avoidance behavior: Differences between Sprague-Dawley and Wistar-Kyoto rats. Behav. Brain Res. (2020 Jun 22[epub ahead of print])  doi: 10.1016/j.bbr.2020.112784.

A reinforcement-learning model of active avoidance behavior: Differences between Sprague Dawley and Wistar-Kyoto rats.

Avoidance behavior is a typically adaptive response performed by an organism to avert harmful situations. Individuals differ remarkably in their tendency to acquire and perform new avoidance behaviors, as seen in anxiety disorders where avoidance becomes pervasive and inappropriate. In rodent models of avoidance, the inbred Wistar-Kyoto (WKY) rat demonstrates increased learning and expression of avoidance compared to the outbred Sprague Dawley (SD) rat. However, underlying mechanisms that contribute to these differences are unclear. Computational modeling techniques can help identify factors that may not be easily decipherable from behavioral data alone. Here, we utilize a reinforcement learning (RL) model approach to better understand strain differences in avoidance behavior. An actor-critic model, with separate learning rates for action selection (in the actor) and state evaluation (in the critic), was applied to individual data of avoidance acquisition from a large cohort of WKY and SD rats. Latent parameters were extracted, such as learning rate and subjective reinforcement value of foot shock, that were then compared across groups. The RL model was able to accurately represent WKY and SD avoidance behavior, demonstrating that the model could simulate individual performance. The model determined that the perceived negative value of foot shock was significantly higher in WKY than SD rats, whereas learning rate in the actor was lower in WKY than SD rats. These findings demonstrate the utility of computational modeling in identifying underlying processes that could promote strain differences in behavioral performance.

Biological links between traumatic brain injury and Parkinson's disease.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

Distinct cellular mediators drive the Janus faces of toll-like receptor 4 regulation of network excitability which impacts working memory performance after brain injury.

The mechanisms by which the neurophysiological and inflammatory responses to brain injury contribute to memory impairments are not fully understood. Recently, we reported that the innate immune receptor, toll-like receptor 4 (TLR4) enhances AMPA receptor (AMPAR) currents and excitability in the dentate gyrus after fluid percussion brain injury (FPI) while limiting excitability in controls. Here, we examine the cellular mediators underlying TLR4 regulation of dentate excitability and its impact on memory performance. In ex vivo slices, astrocytic and microglial metabolic inhibitors selectively abolished TLR4 antagonist modulation of excitability in controls, but not in rats after FPI, demonstrating that glial signaling contributes to TLR4 regulation of excitability in controls. In glia-depleted neuronal cultures from naïve mice, TLR4 ligands bidirectionally modulated AMPAR charge transfer consistent with neuronal TLR4 regulation of excitability, as observed after brain injury. In vivo TLR4 antagonism reduced early post-injury increases in mediators of MyD88-dependent and independent TLR4 signaling without altering expression in controls. Blocking TNFα, a downstream effector of TLR4, mimicked effects of TLR4 antagonist and occluded TLR4 agonist modulation of excitability in slices from both control and FPI rats. Functionally, transiently blocking TLR4 in vivo improved impairments in working memory observed one week and one month after FPI, while the same treatment impaired memory function in uninjured controls. Together these data identify that distinct cellular signaling mechanisms converge on TNFα to mediate TLR4 modulation of network excitability in the uninjured and injured brain and demonstrate a role for TLR4 in regulation of working memory function.

Reduced avoidance coping in male, but not in female rats, after mild traumatic brain injury: Implications for depression.

Although there is evidence that traumatic brain injury (mTBI) induces emotional sequelae in rats, it is unclear whether the phenotype is reminiscent of major depressive disorder (MDD) or posttraumatic stress disorder (PTSD). Three behavioral protocols with oppositional indicators for MDD or PTSD were assessed: acoustic startle responses (ASRs), eyeblink conditioning, and instrumental escape/avoidance (E/A) learning. Female and male rats were exposed to lateral fluid percussion injury (LFPi) consistent with mild TBI (mTBI) or sham (SHAM) surgery. Experiment 1 suggested that the acquisition of the classically conditioned eyeblink responses was unaffected by mTBI infemale and male rats. In Experiment 2, male and female mTBI rats acquired instrumental escape responses similar to their SHAM counterparts. Avoidance expression of female mTBI rats did not differ appreciably from female SHAM rats. However, male mTBI rats expressed avoidance at a lower rate than male SHAM rats over training. Poor coping in male rats emerged with repeated exposure to stress, suggesting that depressive behaviors in mTBI develop over time and with continued demand from stress. Severely attenuated ASRs were evident in female and male mTBI rats compared to respective SHAM rats throughout testing across the two experiments. Overall, signs among the three bidirectional assessments during the subacute period after mTBI were more indicative of MDD-like, than PTSD-like sequelae.

Inhibited Personality Temperaments Translated Through Enhanced Avoidance and Associative Learning Increase Vulnerability for PTSD.

Although many individuals who experience a trauma go on to develop post-traumatic stress disorder (PTSD), the rate of PTSD following trauma is only about 15-24%. There must be some pre-existing conditions that impart increased vulnerability to some individuals and not others. Diathesis models of PTSD theorize that pre-existing vulnerabilities interact with traumatic experiences to produce psychopathology. Recent work has indicated that personality factors such as behavioral inhibition (BI), harm avoidance (HA), and distressed (Type D) personality are vulnerability factors for the development of PTSD and anxiety disorders. These personality temperaments produce enhanced acquisition or maintenance of associations, especially avoidance, which is a criterion symptom of PTSD. In this review, we highlight the evidence for a relationship between these personality types and enhanced avoidance and associative learning, which may increase risk for the development of PTSD. First, we provide the evidence confirming a relationship among BI, HA, distressed (Type D) personality, and PTSD. Second, we present recent findings that BI is associated with enhanced avoidance learning in both humans and animal models. Third, we will review evidence that BI is also associated with enhanced eyeblink conditioning in both humans and animal models. Overall, data from both humans and animals suggest that these personality traits promote enhanced avoidance and associative learning, as well as slowing of extinction in some training protocols, which all support the learning diathesis model. These findings of enhanced learning in vulnerable individuals can be used to develop objective behavioral measures to pre-identify individuals who are more at risk for development of PTSD following traumatic events, allowing for early (possibly preventative) intervention, as well as suggesting possible therapies for PTSD targeted on remediating avoidance or associative learning. Future work should explore the neural substrates of enhanced avoidance and associative learning for behaviorally inhibited individuals in both the animal model and human participants.

Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement.

Psychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. It has recently been appreciated that reinforcement may be separated into consummatory (hedonic), motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, motivation to avoid or escape foot shock or to acquire sucrose was not altered by mTBI. Our results suggest that individuals experiencing mTBI find avoidance of aversive events less reinforcing, and therefore are less apt to utilize proactive control of stress.

Experimental traumatic brain injury results in estrous cycle disruption, neurobehavioral deficits, and impaired GSK3ß/ß-catenin signaling in female rats.

An estimated 2.8 million traumatic brain injuries (TBI) occur within the United States each year. Approximately 40% of new TBI cases are female, however few studies have investigated the effects of TBI on female subjects. In addition to typical neurobehavioral sequelae observed after TBI, such as poor cognition, impaired behavior, and somatic symptoms, women with TBI report amenorrhea or irregular menstrual cycles suggestive of disruptions in the hypothalamic-pituitary-gonadal (HPG) axis. HPG dysfunction following TBI has been linked to poor functional outcome in men and women, but the mechanisms by which this may occur or relate to behavior has not been fully developed or ascertained. The present study determined if TBI resulted in HPG axis perturbations in young adult female Sprague Dawley rats, and whether TBI was associated with cognitive and sensorimotor deficits. Following lateral fluid percussion injury, injured females spent significantly more time in diestrus compared to sham females, consistent with a persistent low sex-steroid hormone state. Injured females displayed significantly reduced 17ß-estradiol (E2) and luteinizing hormone levels. Concomitantly, injured females were impaired in spatial working memory compared to shams. Impaired GSK3ß/ß-catenin signaling related to synaptic changes was evident one-week post-injury in the hippocampus among injured females compared to sham females, and this impairment paralleled the deficits in spatial working memory. Sensorimotor function, as evidenced by suppression of the acoustic startle response, was chronically impaired even after normal estrous cycling resumed. These data demonstrate that TBI results in estrous cycle impairments, memory dysfunction, and perturbations in GSK3ß/ß-catenin signaling, suggesting a potential mechanism for HPG-mediated cognitive impairment following TBI.

Danger and safety signals independently influence persistent pathological avoidance in anxiety-vulnerable Wistar Kyoto rats: A role for impaired configural learning in anxiety vulnerability.

Pathological avoidance behavior in anxiety and anxiety-related disorders has a large role in the persistence and severity of disease. Individuals are cued to avoid potential aversive events by learned danger and safety signals in the environment. Individuals with anxiety demonstrate a bias to utilize danger signals more than safety signals, in contrast to those without these disorders. Therefore, the present study investigated if danger and safety signals differentially influenced persistent avoidance in an animal model of anxiety-vulnerability, the Wistar Kyoto (WKY) rat, relative to the outbred Sprague Dawley (SD) rat. Persistent avoidance was assessed using extinction protocols. When danger or safety signals were present during extinction, WKY rats were slower to extinguish the avoidance response compared to SD rats. In contrast, when danger and safety signals were both present during extinction, WKY and SD rats extinguished at a similar rate. Differences in contextual and configural learning were explored as potential causes of the strain differences in the use of safety and danger signals in avoidance extinction. Strains did not differ in avoidance extinction when context was manipulated. However, WKY rats were impaired in configural learning using a negative patterning task. The results indicate that danger and safety signals may impair avoidance extinction in anxiety-vulnerable individuals due to impaired configural learning. These findings have important implications for understanding the etiology of anxiety disorders and may improve their diagnosis and treatment.

Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders.

Anxiety disorders and posttraumatic stress disorder (PTSD) share a common feature of pathological avoidance behavior. The Wistar Kyoto (WKY) rat has been used as a model of anxiety vulnerability, expressing a behaviorally inhibited temperament, acquiring avoidance behavior more rapidly and displaying extinction-resistant avoidance compared to Sprague Dawley (SD) rats. Subanesthetic levels of ketamine have gained attention as a rapid antidepressant in treatment-resistant depression. While traditional antidepressants are commonly used to treat anxiety disorders and PTSD, the therapeutic utility of ketamine for these disorders is much less understood. The hippocampus is critical for the actions of antidepressants, is a structure implicated in anxiety disorders and PTSD, and is necessary for extinction of avoidance in SD rats. WKY rats have impaired hippocampal long-term potentiation (LTP), suggesting that persistent avoidance in WKY rats may be due to deficient hippocampal synaptic plasticity. In the present study, we hypothesized that ketamine would facilitate extinction of avoidance learning in WKY rats, and do so by enhancing hippocampal synaptic plasticity. As predicted, ketamine facilitated extinction of avoidance behavior in a subset of WKY rats (responders), with effects lasting at least three weeks. Additionally, LTP in these rats was enhanced by ketamine. Ketamine was not effective in facilitating avoidance extinction or in modifying LTP in WKY non-responders. The results suggest that subanesthetic levels of ketamine may be useful for treating anxiety disorders by reducing avoidance behaviors when combined with extinction conditions. Moreover, ketamine may have its long-lasting behavioral effects through enhancing hippocampal synaptic plasticity.

Neurocognitive and Fine Motor Deficits in Asymptomatic Adolescents during the Subacute Period after Concussion.

Adolescents are at high risk for sustaining concussions. There is considerable controversy regarding the sensitivity of neurocognitive tests to detect and track dysfunction in the aftermath of concussion. Two neurocognitive test batteries were compared during the subacute phase of recovery from concussion to determine sensitivity to concussion. Adolescents (ages 11-17 years) with a concussion diagnosis (eight males, seven females, 9-69 days after injury) were recruited through a concussion clinic and compared with community nonconcussed volunteers (11 males, three females). Adolescents completed the online version of the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) on a desktop computer and the Defense Automated Neurobehavioral Assessment (DANA) on a handheld device, as well as the Grooved Pegboard Test, which assessed manual dexterity and motor speed. There were no differences in self-reported symptoms on the Post-Concussion Symptom Scale comparing concussed and nonconcussed adolescents. No significant between-groups differences were observed in ImPACT performance. Performance deficits were apparent for the DANA assessment, reflecting lower throughput scores for simple reaction time and response inhibition parameters in those with concussion. Concussed adolescents also had slower Grooved Pegboard Test performance when using the nondominant hand. Both the DANA test battery and the Grooved Pegboard Test appear to have promise as tools to detect persistent cognitive and motor dysfunction in the subacute period after concussion.

Differential use of danger and safety signals in an animal model of anxiety vulnerability: The behavioral economics of avoidance.

Differential processing of danger and safety signals may underlie symptoms of anxiety disorders and posttraumatic stress disorder. One symptom common to these disorders is pathological avoidance. The present study examined whether danger and safety signals influence avoidance differently in anxiety-vulnerable Wistar-Kyoto (WKY) rats and Sprague Dawley (SD) rats. SD and WKY rats were tested in a novel progressive ratio avoidance task with and without danger or safety signals. Two components of reinforcement, hedonic value and motivation, were determined by fitting an exponentiated demand equation to the data. Hedonic value of avoidance did not differ between SD and WKY rats, but WKY rats had greater motivation to avoid than SD rats. Removal of the safety signal reduced motivation to avoid in SD, but not WKY, rats. Removal of the danger signal did not alter avoidance in either strain. When danger and safety signals were presented simultaneously, WKY rats responded to the danger signals, whereas SD rats responded to the safety signal. The results provide evidence that 1) safety signals enhance motivation to avoid in SD rats, 2) both danger and safety signals influence motivation in WKY rats, and 3) danger signals take precedence over safety signals when presented simultaneously in WKY rats. Thus, anxiety vulnerability is associated with preferential use of danger signals to motivate avoidance. The differential use of danger and safety signals has important implications for the etiology and treatment of pathological avoidance in anxiety disorders and posttraumatic stress disorder.

Corrigendum: Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement.

[This corrects the article on p. 77 in vol. 11, PMID: 28270744.].

Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement.

Abnormal motivation and hedonic assessment of aversive stimuli are symptoms of anxiety and depression. Symptoms influenced by motivation and anhedonia predict treatment success or resistance. Therefore, a translational approach to the study of negatively motivated behaviors is needed. We describe a novel use of behavioral economics demand curve analysis to investigate negative reinforcement in animals that separates hedonic assessment of footshock termination (i.e., relief) from motivation to escape footshock. In outbred Sprague Dawley (SD) rats, relief increased as shock intensity increased. Likewise, motivation to escape footshock increased as shock intensity increased. To demonstrate the applicability to anxiety disorders, hedonic and motivational components of negative reinforcement were investigated in anxiety vulnerable Wistar Kyoto (WKY) rats. WKY rats demonstrated increased motivation for shock cessation with no difference in relief as compared to control SD rats, consistent with a negative bias for motivation in anxiety vulnerability. Moreover, motivation was positively correlated with relief in SD, but not in WKY. This study is the first to assess the hedonic and motivational components of negative reinforcement using behavioral economic analysis. This procedure can be used to investigate positive and negative reinforcement in humans and animals to gain a better understanding of the importance of motivated behavior in stress-related disorders.

Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus.

Mild traumatic brain injury (mTBI) can produce somatic symptoms such as headache, dizziness, fatigue, sleep disturbances and sensorimotor dysfunction. Sensorimotor function can be measured by tests such as the acoustic startle reflex (ASR), an evolutionarily conserved defensive response to a brief yet sharp acoustic stimulus. mTBI produces a long-lasting suppression of ASR in rodents and humans; however, the mechanism of this suppression is unknown. The present study examined whether inflammatory processes in the brainstem (particularly the caudal pontine reticular nucleus, PnC) could account for the suppression of ASR after mTBI, because the PnC is an essential nucleus of the ASR circuit. Furthermore, while inflammation after mTBI is commonly observed in brain regions proximal to the site of impact (cortex and hippocampus), the effects of mTBI in brainstem structures remains largely understudied. The present study demonstrated a suppression of ASR one day after injury and lasting at least three weeks after an mTBI, replicating previous findings. Within the PnC, transient elevations of IL-1ß and TNF-α mRNA were observed at one day after injury, while IL-1α mRNA exhibited a delayed increase at three weeks after injury. Reactive gliosis (via IBA-1-ir for microglia and GFAP-ir for astrocytes) were also observed in the PnC, at one day and seven days after injury, respectively. Finally, the number of giant neurons (the major functional cell population in the PnC) was decreased three weeks after injury. The results indicate that glial activation precedes neuronal loss in the PnC, and correlates with the behavioral suppression of the ASR. The results also raise implications for brainstem involvement in the development of post-traumatic symptoms.

Brain and Serum Androsterone Is Elevated in Response to Stress in Rats with Mild Traumatic Brain Injury.

Exposure to lateral fluid percussion (LFP) injury consistent with mild traumatic brain injury (mTBI) persistently attenuates acoustic startle responses (ASRs) in rats. Here, we examined whether the experience of head trauma affects stress reactivity. Male Sprague-Dawley rats were matched for ASRs and randomly assigned to receive mTBI through LFP or experience a sham surgery (SHAM). ASRs were measured post injury days (PIDs) 1, 3, 7, 14, 21, and 28. To assess neurosteroids, rats received a single 2.0 mA, 0.5 s foot shock on PID 34 (S34), PID 35 (S35), on both days (2S), or the experimental context (CON). Levels of the neurosteroids pregnenolone (PREG), allopregnanolone (ALLO), and androsterone (ANDRO) were determined for the prefrontal cortex, hippocampus, and cerebellum. For 2S rats, repeated blood samples were obtained at 15, 30, and 60 min post-stressor for determination of corticosterone (CORT) levels after stress or context on PID 34. Similar to earlier work, ASRs were severely attenuated in mTBI rats without remission for 28 days after injury. No differences were observed between mTBI and SHAM rats in basal CORT, peak CORT levels or its recovery. In serum and brain, ANDRO levels were the most stress-sensitive. Stress-induced ANDRO elevations were greater than those in mTBI rats. As a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, increased brain ANDRO levels are expected to be anxiolytic. The impact of brain ANDRO elevations in the aftermath of mTBI on coping warrants further elaboration.

Paired-housing selectively facilitates within-session extinction of avoidance behavior, and increases c-Fos expression in the medial prefrontal cortex, in anxiety vulnerable Wistar-Kyoto rats.

OBJECTIVE: The perseveration of avoidance behavior, even in the absence of once threatening stimuli, is a key feature of anxiety and related psychiatric conditions. This phenomenon can be observed in the Wistar-Kyoto (WKY) rat which, in comparison to outbred controls, demonstrates impaired extinction of avoidance behavior. Also characteristic of the WKY rat is abnormalities of the neurocircuitry and neuroplasticity of the medial prefrontal cortex (mPFC). One means of reducing physiological responses to anxiety, and conditioned fear, in social species is the presence of a conspecific animal. The current study investigates whether or not pair-housed WKY rats would show facilitated extinction of avoidance in comparison to individual-housed WKY rats, and whether or not pair-housing influences mPFC activation during lever-press avoidance. METHODS: Male WKY rats were assigned to individual-housed and pair-housed conditions. Rats were trained in lever-press avoidance. Each session of lever-press avoidance consisted of 20 trials, where pressing a lever in response to a warning tone prevented foot-shocks. Rats received 12 acquisition sessions over 4weeks; followed by 6 extinction sessions over 2weeks, where foot-shocks ceased to be delivered. Brains were harvested 90min after trials 1 and 10 of extinction sessions 1 and 6, and mPFC sections underwent c-Fos staining as a measure of activation. RESULTS: Pair-housed rats showed facilitated lever-press avoidance extinction rates, but the main cause for this overall difference was a selective facilitation of within-session extinction. Similar to individual-housed rats, pair-housed rats continued to avoid during trial 1 of extinction even when the avoidance responding had been significantly reduced by the end of the previous session. Pair-housed rats sacrificed on trial 1 showed greater c-Fos expression in the anterior cingulate cortex and prelimbic cortex subregions of the mPFC compared individual-housed rats sacrificed on trial 1. CONCLUSION: This data shows pair-housing to facilitate the extinction of avoidance, and to influence activity of the mPFC, in WKY rats. Despite this environmental manipulation, the pair-housed WKY rats continued to show avoidance responding on trial 1 of extinction sessions. This demonstrates that within-session extinction can be dissociated from between-session extinction-resistance in WKY rats. Furthermore, it suggests the individual-housing of WKY rats selectively slows within-session extinction, possibly by reducing neuronal activity of the mPFC during the testing situation.

Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability.

Individuals exhibiting an anxiety disorder are believed to possess an innate vulnerability that makes them susceptible to the disorder. Anxiety disorders are also associated with abnormalities in the interconnected brain regions of the amygdala and prefrontal cortex (PFC). However, the link between anxiety vulnerability and amygdala-PFC dysfunction is currently unclear. Accordingly, the present study sought to determine if innate dysfunction within the amygdala to PFC projection underlies the susceptibility to develop anxiety-like behavior, using an anxiety vulnerable rodent model. The inbred Wistar Kyoto (WKY) rat was used to model vulnerability, as this strain naturally expresses extinction-resistant avoidance; a behavior that models the symptom of avoidance present in anxiety disorders. Synaptic plasticity was assessed within the projection from the basolateral nucleus of the amygdala (BLA) to the prelimbic cortical subdivision of the PFC in WKY and Sprague Dawley (SD) rats. While WKY rats exhibited normal paired-pulse plasticity, they did not maintain long-term potentiation (LTP) as SD rats. Thus, impaired plasticity within the BLA-PL cortex projection may contribute to extinction resistant avoidance of WKY, as lesions of the PL cortex in SD rats impaired extinction of avoidance similar to WKY rats. Treatment with d-cycloserine to reverse the impaired LTP in WKY rats was unsuccessful. The lack of LTP in WKY rats was associated with a significant reduction of NMDA receptors containing NR2A subunits in the PL cortex. Thus, dysfunction in amygdala-PFC plasticity is innate in anxiety vulnerable rats and may promote extinction-resistant avoidance by disrupting communication between the amygdala and prefrontal cortex.

Leukemia Inhibitory Factor Haplodeficiency Desynchronizes Glial Reactivity and Exacerbates Damage and Functional Deficits after a Concussive Brain Injury.

Reactions of both astrocytes and microglia to central nervous system injury can be beneficial or detrimental to recovery. To gain insights into the functional importance of gliosis, we developed a new model of adolescent closed-head injury (CHI) and interrogated the behavioral, physiological, and cellular outcomes after a concussive CHI in leukemia inhibitory factor (LIF) haplodeficient mice. These mice were chosen because LIF is important for astrocyte and microglial activation. Behaviorally, the LIF haplodeficient animals were equally impaired 4 h after the injury, but in the subsequent 2 weeks, the LIF haplodeficient mice acquired more severe motor and sensory deficits, compared with wild type mice. The prolonged accumulation of neurological impairment was accompanied by desynchronization of the gliotic response, increased cell death, axonal degeneration, diminished callosal compound action potential, and hypomyelination. Our results clearly show that LIF is an essential injury-induced cytokine that is required to prevent the propagation of secondary neurodegeneration.

Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task.

Altered medial prefrontal cortex (mPFC) and amygdala function is associated with anxiety-related disorders. While the mPFC-amygdala pathway has a clear role in fear conditioning, these structures are also involved in active avoidance. Given that avoidance perseveration represents a core symptom of anxiety disorders, the neural substrate of avoidance, especially its extinction, requires better understanding. The present study was designed to investigate the activity, particularly, inhibitory neuronal activity in mPFC and amygdala during acquisition and extinction of lever-press avoidance in rats. Neural activity was examined in the mPFC, intercalated cell clusters (ITCs) lateral (LA), basal (BA) and central (CeA) amygdala, at various time points during acquisition and extinction, using induction of the immediate early gene product, c-Fos. Neural activity was greater in the mPFC, LA, BA, and ITC during the extinction phase as compared to the acquisition phase. In contrast, the CeA was the only region that was more activated during acquisition than during extinction. Our results indicate inhibitory neurons are more activated during late phase of acquisition and extinction in the mPFC and LA, suggesting the dynamic involvement of inhibitory circuits in the development and extinction of avoidance response. Together, these data start to identify the key brain regions important in active avoidance behavior, areas that could be associated with avoidance perseveration in anxiety disorders.