Examining the long-term effects of traumatic brain injury on fear extinction in male rats.

There is a strong association between traumatic brain injuries (TBIs) and the development of psychiatric disorders, including post-traumatic stress disorder (PTSD). Exposure-based therapy is a first-line intervention for individuals who suffer from PTSD and other anxiety-related disorders; however, up to 50% of individuals with PTSD do not respond well to this approach. Fear extinction, a core mechanism underlying exposure-based therapy, is a procedure in which a repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus leads to a decrease in fear expression, and is a useful tool to better understand exposure-based therapy. Identifying predictors of extinction would be useful in developing alternative treatments for the non-responders. We recently found that CO2 reactivity predicts extinction phenotypes in rats, likely through the activation of orexin receptors in the lateral hypothalamus. While studies have reported mixed results in extinction of fear after TBI, none have examined the long-term durability of this phenotype in the more chronically injured brain. Here we tested the hypothesis that TBI results in a long-term deficit in fear extinction, and that CO2 reactivity would be predictive of this extinction phenotype. Isoflurane-anesthetized adult male rats received TBI (n = 59) (produced by a controlled cortical impactor) or sham surgery (n = 29). One month post-injury or sham surgery, rats underwent a CO2 or air challenge, followed by fear conditioning, extinction, and fear expression testing. TBI rats exposed to CO2 (TBI-CO2) showed no difference during extinction or fear expression relative to shams exposed to CO2 (sham-CO2). However, TBI-CO2 rats, showed significantly better fear expression than TBI rats exposed to air (TBI-air). In contrast to previous findings, we observed no relationship between CO2 reactivity and post-extinction fear expression in either the sham or TBI rats. However, compared to the previously observed naïve sample, we observed more variability in post-extinction fear expression but a very similar distribution of CO2 reactivity in the current sample. Isoflurane anesthesia may lead to interoceptive threat habituation, possibly via action on orexin receptors in the lateral hypothalamus, and may interact with CO2 exposure, resulting in enhanced extinction. Future work will directly test this possibility.

Extinction to amphetamine-associated context in female rats is dependent upon conditioned orienting.

RATIONALE: Females are considered more susceptible to the reinforcing effects of drugs and subsequently at increased risk for drug abuse and relapse after treatment. Estrogen is known to facilitate drug effects in females. However, other factors which contribute to the incidence of drug abuse are important to identify in order to recognize early risk factors and develop effective prevention and treatment schemes. Cue-directed behavior (aka sign tracking) has been implicated as a behavioral phenotype which identifies populations susceptible to drug abuse, partly due to its association with impulsivity and heightened dopamine function. OBJECTIVES AND METHODS: In this study, we investigate the viability of conditioned orienting (a form of cue-directed behavior) as a potential phenotype which predicts drug proclivity in female rats. In addition, we examine any influence endogenous female hormones across the estrous cycle may have on conditioned orienting and drug proclivity. RESULTS AND CONCLUSIONS: Utilizing an amphetamine-conditioned place preference task, results suggest that the orienting phenotype is an effective predictor of drug proclivity in females. Rats exhibiting enhanced orienting behavior show more robust preference for an amphetamine-associated context and are more resistant to extinction of this preference than nonorienting counterparts. Furthermore, both conditioned orienting behavior and conditioned place preference are minimally influenced by the estrous cycle.

Predicting extinction phenotype to optimize fear reduction.

Fear conditioning is widely employed to study dysregulations of the fear system. The repeated presentation of a conditioned stimulus in the absence of a reinforcer leads to a decrease in fear responding-a phenomenon known as extinction. From a translational perspective, identifying whether an individual might respond well to extinction prior to intervention could prove important to treatment outcomes. Here, we test the hypothesis that CO2 reactivity predicts extinction phenotype in rats, and that variability in CO2 reactivity as well as extinction long-term memory (LTM) significantly predicts orexin activity in the lateral hypothalamus (LH). Our results validate a rat model of CO2 reactivity and show that subcomponents of behavioral reactivity following acute CO2 exposure explain a significant portion of the variance in extinction LTM. Furthermore, we show evidence that variability in CO2 reactivity is also significantly predictive of orexin activity in the LH, and that orexin activity, in turn, significantly accounts for LTM variance. Our findings open the possibility that we may be able to use CO2 reactivity as a screening tool to determine if individuals are good candidates for an extinction/exposure-based approach.

The roots of empathy: Through the lens of rodent models.

Empathy is a phenomenon often considered dependent on higher-order emotional control and an ability to relate to the emotional state of others. It is, by many, attributed only to species having well-developed cortical circuits capable of performing such complex tasks. However, over the years, a wealth of data has been accumulated showing that rodents are capable not only of sharing emotional states of their conspecifics, but also of prosocial behavior driven by such shared experiences. The study of rodent empathic behaviors is only now becoming an independent research field. Relevant animal models allow precise manipulation of neural networks, thereby offering insight into the foundations of empathy in the mammalian brains. Here we review the data on empathic behaviors in rat and mouse models, their neurobiological and neurophysiological correlates, and the factors influencing these behaviors. We discuss how simple rodent models of empathy enhance our understanding of how brain controls empathic behaviors.

Differential expression of basic fibroblast growth factor-2 in the developing rat brain.

Basic fibroblast growth factor-2 is a trophic molecule involved in a number of functions within the CNS, including the regulation of CNS responses to injury. Prior studies suggest that rats recover differently from injury inflicted to different regions and at different ages throughout development, and that basic fibroblast growth factor-2 may, at least in part, underlie this phenomenon. In the present study, we describe the distribution of basic fibroblast growth factor-2 at postnatal days 0, 2, 6, 10, 12, 14, 18, 21 and 30 in the indusium griseum, the external capsule, the hippocampus, the medial prefrontal cortex, the motor cortex, the rostral migratory stream, and the subventricular zone. Our results suggest a differential temporal and spatial expression of basic fibroblast growth factor-2 throughout development, which may explain the differential recovery observed from cortical lesions inflicted at different time points after birth.

The aging hippocampus: a multi-level analysis in the rat.

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.

Basic fibroblast growth factor stimulates functional recovery after neonatal lesions of motor cortex in rats.

Rats were given bilateral lesions of the motor cortex on the tenth day of life, and then received a daily subcutaneously injection of either basic fibroblast growth factor (FGF-2) or vehicle for 7 consecutive days. In adulthood, they were trained and assessed on a skilled forelimb reaching task. Although all lesion groups were impaired at skilled reaching, the postnatal day 10-lesioned group that received FGF-2 was less impaired than the lesion group that received the vehicle. Furthermore, the lesioned rats that received FGF-2 showed a filling of the lesion cavity with tissue, whereas the lesioned vehicle-treated rats still had a prominent lesion cavity. The functionality of the tissue filling the cavity, tissue surrounding it, and tissue from the motor cortex (in control rats) was assessed using intracortical microstimulation, and showed that stimulation of some sites from the filled cavity could evoke movement. The rats were perfused and processed for Golgi-Cox staining. Medium spiny neurons from the striatum were drawn and analyzed, and the results suggest that postnatal day 10 lesions of the motor cortex induced an increase in the length and complexity of these cells compared with those of non-lesioned rats. Our results suggest that FGF-2 may play an important role in recovery from early brain damage.

Skilled-learning-induced potentiation in rat sensorimotor cortex: a transient form of behavioural long-term potentiation.

The relation between the acquisition of a skilled motor task and synaptic plasticity in the sensorimotor cortex of the awake, freely behaving rat was examined. Skilled-motor training was previously found to induce a functional reorganization of the caudal forelimb area, and to induce an increase in synaptic efficacy, measured in vitro, on the side contralateral to the reaching forelimb. Here, we repeatedly measured neocortical evoked potential recordings in awake, freely behaving rats to examine whether skilled training would induce changes in polysynaptic efficacy on the side contralateral to the reaching forelimb. We found that the increase in task proficiency, but not the acquisition of task requirements or the maintenance of task proficiency, induced an increase in synaptic efficacy on the side contralateral to the reaching forelimb. We also tested the hypothesis that skilled learning induced potentiation shares similar mechanisms to long-term potentiation (LTP) and long-term depression by artificially manipulating polysynaptic efficacy in skilled rats with high- and low-frequency stimulation. We observed that, compared with the ipsilateral side, less potentiation but more depression could be induced on the side contralateral to the reaching forelimb. We conclude that a transient, network-based LTP-like mechanism operates during the learning of a skilled motor task.