Kevin D. Beck

Avoidance perseveration during extinction training in Wistar-Kyoto rats: an interaction of innate vulnerability and stressor intensity.

Given that avoidance is a core feature of anxiety disorders, Wistar-Kyoto (WKY) rats may be a good model of anxiety vulnerability for their hypersensitivity to stress and trait behavioral inhibition. Here, we examined the influence of strain and shock intensity on avoidance acquisition and extinction. Accordingly, we trained WKY and Sprague-Dawley (SD) rats in lever-press avoidance using either 1.0-mA or 2.0-mA foot-shock. After extinction, neuronal activation was visualized by c-Fos for overall activity and parvalbumin immunoreactivity for gamma-aminobutyric acid (GABA) neuron in brain areas linked to anxiety (medial prefrontal cortex and amygdala). Consistent with earlier work, WKY rats acquired lever-press avoidance faster and to a greater extent than SD rats. However, the intensity of foot shock did not differentially affect acquisition. Although there were no differences during extinction in SD rats, avoidance responses of WKY rats trained with the higher foot shock perseverated during extinction compared to those WKY rats trained with lower foot shock intensity or SD rats. WKY rats trained with 2.0-mA shock exhibited less GABAergic activation in the basolateral amygdala after extinction. These findings suggest that inhibitory modulation in amygdala is important to ensure successful extinction learning. Deficits in avoidance extinction secondary to lower GABAergic activation in baslolateral amygdala may contribute to anxiety vulnerability in this animal model of inhibited temperament.

Classical and instrumental conditioning of eyeblink responses in Wistar–Kyoto and Sprague–Dawley rats

Wistar-Kyoto (WKY) rats, an animal model of anxiety vulnerability, acquire lever-press avoidance faster than outbred Sprague-Dawley (SD) rats. Faster avoidance acquisition may reflect an inherent ability to acquire cue-outcome associations, response-outcome associations or both. To evaluate cue-outcome learning, acquisition of classically conditioned eyeblink response was compared in SD and WKY rats using a delay-type paradigm (500-ms conditioned stimulus (CS) coterminating with a 10-ms unconditional stimulus (US)). WKY rats demonstrated enhanced classical conditioning, with both faster acquisition and greater asymptotic performance in delay-type training than SD rats. To evaluate response-outcome learning, separate SD and WKY rats were given control over US delivery through imposition of an omission contingency into delay-type training (emitting a conditioned response (CR) prevented delivery of the US). The schedule of US delivery derived by these rats became the training regimen for a separate group of SD and WKY rats, yoked within strain. In SD rats, no differences in acquisition were detected between those given control over US delivery and those trained with the same partial reinforcement schedule. Acquisition rates of those WKY rats with control exceeded those trained with a yoked-schedule of US presentation. Collectively, WKY rats exhibit enhanced classical conditioning and sensitivity to schedules of reinforcement compared to outbred SD rats. Anxiety vulnerability, in particular inhibited temperament, may be traced to active processes in the prediction and control of aversive events.

Deficient proactive interference of eyeblink conditioning in Wistar-Kyoto rats.

Wistar-Kyoto (WKY) rats exhibit behavioral inhibition and model anxiety vulnerability. Although WKY rats exhibit faster active avoidance acquisition, simple associative learning or the influence of proactive interference (PI) has not been adequately assessed in this strain. Therefore, we assessed eyeblink conditioning and PI in WKY and outbred Sprague-Dawley (SD) rats. Rats were pre-exposed to either the experimental context, the conditioned stimulus (CS), the unconditional stimulus (US), or the CS & US in an explicitly unpaired (EUP) manner, to examine latent inhibition (LI), US pre-exposure effect, or learned irrelevance (LIRR), respectively. Immediately following pre-exposures, rats were trained in a delay-type paradigm (500 ms CS coterminating with a 10-ms US) for one session. During training SD rats exhibited LI and inhibition from US pre-exposures without evidence of LIRR. PI was less evident in WKY rats; LI was absent in WKY rats. Even in the context of reduced PI to CS-alone and US-alone pre-exposures, LIRR was not apparent in WKY rats. The more normal acquisition rates exhibited by WKY rats, under conditions which degrade performance in SD rats, increases the overall likelihood for WKY rats to acquire defensive responses. Enhanced acquisition of defensive responses is a means by which anxiety vulnerability (e.g., behavioral inhibition) is translated to anxiety psychopathology.

Toll-like receptor 9 deficiency impacts sensory and motor behaviors

Toll-like receptors (TLRs) mediate the induction of the innate immune system in response to pathogens, injury and disease. However, they also play non-immune roles and are expressed in the central nervous system (CNS) during prenatal and postnatal stages including adulthood. Little is known about their roles in the CNS in the absence of pathology. Several members of the TLR family have been implicated in the development of neural and cognitive function although the contribution of TLR9 to these processes has not been well defined. The current studies were undertaken to determine whether developmental TLR9 deficiency affects motor, sensory or cognitive functions. We report that TLR9 deficient (TLR9(-/-)) mice show a hyper-responsive sensory and motor phenotype compared to wild type (TLR9(+/+)) controls. This is indicated by hypersensitivity to thermal stimuli in the hot plate paw withdrawal test, enhanced motor-responsivity under anxious conditions in the open field test and greater sensorimotor reactivity in the acoustic startle response. Prepulse inhibition (PPI) of the acoustic startle response was also enhanced, which indicates abnormal sensorimotor gating. In addition, subtle, but significant, gait abnormalities were noted in the TLR9(-/-) mice on the horizontal balance beam test with higher foot slip numbers than TLR9(+/+) controls. In contrast, spatial learning and memory, assessed by the Morris water maze, was similar in the TLR9(-/-) and TLR9(+/+) mice. These findings support the notion that TLR9 is important for the appropriate development of sensory and motor behaviors.

Acquisition of Active Avoidance Behavior as a Precursor to Changes in General Arousal in an Animal Model of PTSD

1.1 Increased defensive reactions as a sign of PTSD Post-traumatic stress disorder (PTSD) is a multi-symptom condition that includes three primary psychological features: reexperiencing, avoidance and emotional numbing, and hyperarousal (American Psychiatric Association, 2000). Historically, reexperiencing and hyperarousal have been the most studied features, from a neurobiological perspective, using various animal models. In these animal models, changes in defensive reflexive behaviors serve as the assessment measures for these symptoms; thus, both startle reactivity and freezing are now commonly used measures. Freezing behavior is advantageous because of its easy implementation; either the naked eye or an automated motor-tracking system can determine the duration and/or frequency of freezing behavior. In addition, freezing can occur in response to a specific fear-eliciting stimulus or to a fear-experienced context (Doyle & Yule, 1959; Bouton & Bolles, 1980; Fanselow, 1980). Because of these stimulus-response properties, freezing is the response commonly used to assess the experiencing of memories of conditioned stimuli that previously caused a heightened state of fear. At times, the acoustic startle response is used as an assessment of stimulus-elicited fear reactions (Davis, 1986; Hitchcock & Davis, 1987). Under this guise, similar stimuli used in conditioned freezing are experienced by the animal prior to a quick onset, relatively loud, acoustic stimulus. The result is a startle response that is enhanced over baseline levels, which is termed fear-potentiated startle. However, in the case of PTSD, arousal is not necessarily tied to a memory or triggered by an explicit learned association. There are several examples of patients with PTSD exhibiting exaggerated startle responses in the absence of a known trigger (Butler et al., 1990; Orr et al., 1995; Yehuda et al., 1998; Orr et al., 2002). In fact, human longitudinal studies have found changes in startle reactivity occur over a period of time following the associated trauma (Shalev et al., 1998). Although there are possible confounding variables with any repeated test, such as developing an aversion to the startle testing context, there is a difference with PTSD patients as they fail to habituate to the startle test over months (Shalev et al., 1998). Increases in startle magnitudes can be elicited in rats in order to model this feature of PTSD by exposing them to inescapable shock. Interestingly, like some of the symptoms of PTSD,

Effects of a single green flash versus a white flash of light on saccadic oculomotor metrics

White light encompasses all wavelengths of the visible optical spectrum while variations of green light cover only a fraction. Saccades comprise a considerable portion of ocular activity and have been used for research in neurology, cognitive processing, reading, and weaponry design. The goal of this experiment was to study how different energies of light affect the saccadic oculomotor system. This was tested by white and green photic stimulation in eleven and eight subjects respectively as they visually attempted to locate a target. The subject was presented with a target: 15 degrees to either the right or left from the midline with no photic stimulus (control), 15 degrees to the right or left accompanied by a photic stimulus at: midline, 15 degrees to the left, or 15 degrees to the right. Data were collected using the Skalar infrared limbic tracking system and a custom LabVIEW program. Dynamics were quantified with a latency analysis and the time to acquire /spl plusmn/ one degree of the target analysis using MatLAB. Results show that an increase in latency occurs during target location accompanied by a photic stimulus compared to target location accompanied by no photic stimulus, and that green light has a more robust effect on saccadic metrics than white light.

The use of a videogame for assessing sensory-motor and cognitive interference effects in humans

Light is a reliable visual distracter. Our research program is geared toward documenting the parameters by which different forms of light cause distraction in basic sensory-perception processes, motor abilities, and mental capabilities (sample classification, sample identification, trail markings short-term memory, etc.) Unlike the standardized assessment tests commonly used, we theorized that a videogame-type task would allow for multiple-trial measurements in tasks similar to what is assessed in the Wechsler Abbreviated Intelligence Scale. To determine if the commercial video game Police Trainer could be used as the videogame research tool we correlated measures of short-term memory (Wechsler Abbreviated Intelligence Scale) and sensory-motor processing (Grooved Pegboard) with tasks played In the game. We found that scores on specific tasks increased at different rates depending on the task complexity (simple visual-motor versus class identification or short-term memory). We concluded that the use of this videogame has utility as an active-assessment tool especially in studies where additional attention or cognitive load manipulations (such as visual or auditory distracters) are of primary interest We have now proceeded in implementing the video game into a light-distracting experiment. White light is presented. as the visual distracter from several angles, in reference to the games screen. As participants play the assigned tasks, an occasional 1 s flash of light is presented. Accuracy and latency to respond to the game-task is measured on the light-exposure trials versus the no-exposure trials. Behavioral reactions to the light stimuli were recorded using mini cameras in the room and on the game. Pilot data from the light exposure trials are presented.

Brief intermittent light stimulation disrupts saccadic oculomotor control

Purpose:  This study sought to determine the effect of very brief, single and multiple pulses of light on spatial and temporal aspects of saccadic eye movements.

Cholinergic overstimulation supports conditioned-facilitated startle but not conditioned hyperalgesia.

Pyridostigmine bromide (PB), a peripheral cholinesterase inhibitor, has been shown to support odor-potentiated startle responding in rats. Here we conducted 2 sets of experiments that further characterize aspects of this learned association. First we conducted experiments designed to further characterize the learning parameters of the odor-PB association that leads to startle facilitation weeks later. We found that an acute injection of PB causes an increase in startle reactivity that lasts less than 2 h. This is evidence for PBs direct action on the startle response as an enhancing agent. We also delineated the duration of the conditioned enhancement to less than 4 weeks. Second, we conducted similar studies but substituted a nociceptive paw-lick response (thermal pain reflex) for the startle reflex. PB did not have an unconditional action upon the latency to paw-lick to a 48.5 degrees C heated plate nor did any subsequent changes in paw-lick occur in the presence of the previously paired odor. These results suggest that the actions of PB, as an unconditional stimulus, are limited to specific behaviors. Future work examining this compound as a source of conditioned symptoms (as in the case of Gulf War Illness) should focus on those symptoms that are directly influenced by peripheral cholinergic activity.

Suppression through acoustics

This paper reviews research conducted by our laboratory exploring the possible use of acoustical stimuli as a tool for influencing behavior. Over the course of several programs, different types of acoustic stimuli have been evaluated for their effectiveness in disrupting targeting, balance, and high-order cognitive processes in both humans and animals. Escape responses are of particular use in this regard. An escape response serves not only as an objective measure of aversion, but as a potential substitute for ongoing behavior. We have also assessed whether the level of performance changes if the individual does not perform an escape response. In general these studies have both suggested certain types of sounds are more aversive or distracting than others. Although the laboratory development of additional stimuli needs to continue, we are taking the next step by testing some of the more effective stimuli in more applied experimental scenarios including those involving group dynamics.