Abstracts/Posters

These are posters presented by members of the Neurogenetics and Behavior Center at various conferences over the past few years. In order to view these posters, you must have Adobe Acrobat installed on your computer.

2008 | 2007 | 2006 | 2005 | NCRR

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Society for Neuroscience Conference 2008

Examining the role of effort-related functions on reward palatability and incentive learning
A. W. JOHNSON, M. GALLAGHER, P. C. HOLLAND
Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD

Most reinforcement theories suggest that animals typically prefer to exert less effort rather than more in order to obtain food reward (e.g., Hull, 1943). Alternatively, it has been suggested that the degree of effort exerted for a particular commodity enhances the value attributed to it. The effects of effort on preference for a primary reinforcer were examined using a novel paradigm that required mice to respond on two separate levers for two different rewards, whereby each response results in delivery of a specific reward on a fixed-ratio-1 (FR-1 schedule). After acquisition, the response-reinforcement schedule was made gradually more strict for one lever (i.e., increasing to FR15; high-effort schedule), while the schedule for the other lever remains fixed at FR-1 (low-effort schedule). At test, mice showed preferential consumption of the reward that was associated with the high-effort schedule (Experiment 1). In Experiment 2, auditory cues were presented during reward delivery on the high- and low-effort schedules. Subsequently, the effectiveness of these cues to reinforce new nose-poke learning (i.e., conditioned reinforcement) was assessed. Under these conditions, mice showed a preference for the nose-poke associated with presentations of the high-effort cue. In Experiment 3, baseline consumption tests were initially conducted using either higher-caloric (e.g., 6% polycose solution) or lower-caloric (e.g., 2% polycose solution) solutions. Typically mice showed greater consumption of the high- vs. low-caloric reward. Mice were then trained to respond under high- or low-effort conditions for either the high- or low-caloric reward. At test, mice consumed significantly more of the low-caloric reward when it was associated with the high-effort schedule, but not when this reward was associated with the low-effort schedule. Finally, the dopamine antagonist Haloperidol was used to evaluate the pharmacology associated with this effect. Our results are consistent with the proposition that reward value is functionally related to the amount of effort required to obtain it.

Funded by NIH (P40RR017688)

A necessary role for Darpp-32 in incentive salience attribution
Hans S. Crombag^1,2, Janna J. Johnson^1,2, Alexander W. Johnson^1,2, Allen A. Fienberg³, Paul Greengard³, Peter C. Holland^1,2, Michela Gallagher^1,2
1Neurogenetics and Behavior Center,
²Department of Psychological and Brain Sciences, The Johns Hopkins University, Baltimore, MD;
³Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY

Dopamine and cyclic-AMP regulated phosphoprotein-32 (Darpp-32) is selectively enriched in dopamine-receptor expressing forebrain neurons, including medium spiny neurons of the nucleus accumbens and neurons of the central nucleus of the amygdala. When phosphorylated at Thr34, Darpp-32 acts as a potent inhibitor of protein phosphatase 1 (PP1) activity and subsequently as an amplifier of PKA-mediated signal transduction. This amplifying property of DARPP-32 is critical for dopamine-receptor mediated signal transduction, as well as for the actions of other neurotransmitters (e.g. glutamate) on neuronal function. In light of these anatomical and functional characteristics of Darpp-32, we hypothesized that Darpp-32 plays an important role in a form of incentive learning known to be dependent on dopamine and glutamate receptor activation, and the integrity of subregions of the accumbens and amygdala. Mice lacking Darpp-32 (KO) and wildtype (WT) controls were first trained on a Pavlovian conditioning task to associate an auditory cue with reward delivery (CS+) and then the ability of the CS+ to subsequently energize or potentiate ongoing instrumental responding was assessed – a phenomenon known as Pavlovian-to-instrumental transfer or PIT. Whilst Darpp-32 KO mice were capable of acquiring the simple cue-reward association, when subsequently tested for PIT, Darpp-32 KO mice failed to show the typical CS+ induced potentiation of instrumental responding that was seen in WT control mice. Interestingly, a parallel experiment revealed that the Darpp-32 associated deficit was highly selective to PIT as other aspects of reward learning (conditioned reinforcement) were unaffected by the Darpp-32 mutation. Our findings provide the first evidence for a role of the Darpp-32 signaling pathway, presumably within the accumbens and central nucleus of the amygdala, in a specific form of incentive learning involved in motivated behavior. Moreover, as PIT is thought to model aspects of psychological processes altered in a number of psychopathological conditions, such as schizophrenia and drug addiction, our findings provide new insights into the proposed role of Darpp-32 in these conditions.
Funded by NIH (P40RR017688)

Consummatory reward-based learning protocols rely on the subject’s willingness to consume the solution/substance being offered. In the current study, we examined the preference for three types of solutions (sweet, starch, and fat) and the effectiveness of each solution as a reinforcer. We used three strains of mice commonly used to generate genetically modified mice (C57BL/6; C57, 129/SvImJ; 129, and an F1 hybrid strain derived from the crossing of the two; F1). Understanding such strain differences is crucial in the field of mouse genetics because a wide array of background strains are used to generate mutant mice. All training and testing occurred in 3 phases and all strains of mice were trained and tested with each taste solution (reward) in the order sucrose, polycose, lecithin. Firstly, in phase 1, to determine the palatability of each reward we measured the number of licks made and the number of entries into the food cup during 30 minutes free access to 1 of 5 concentrations of reward (0, 2.5, 5, 10, and 20% for sucrose and polycose; 0, 1.25, 2.5, 3.75, and 5% for lecithin) for a total of 5 sessions. Each session mice received one concentration of a particular reward, such that by the 5th session mice had received access to all reward concentrations. During the second phase the mice learned to press a lever to dispense the mid-range concentration of the reward. The second phase was carried out over 5 sessions. On completion, mice that failed to reach a criterion of 50 rewards per session were subsequently excluded from the final phase of testing. During the final phase each reward was tested for its effectiveness as a reinforcer under progressive ratio conditions. Our results are consistent with previous reports that there are strain differences in sucrose preference, however we did not observe any strain differences in preference for polycose or lecithin. Results from the progressive ratio procedure revealed strain differences for sucrose and lecithin, but not for polycose. The implications for neurogenetics of using specific taste solutions in consumption-based and instrumental-response-based measures across a range of genetic backgrounds are discussed.
Funded by NCRR (P40RR017688)

Society for Neuroscience Conference 2007

Previous studies, including our own, suggest that CB1 receptor activation plays an important modulatory role in appetitive and consummatory behaviors for food and non-food rewards. Thus, reward sensitivity is altered by pharmacological and genetic targeting of CB1 receptor, as indicated by changes in instrumental responding for reward and consumption once reward is available. Additionally, we have found that the normal ability of Pavlovian reward cues to modulate appetitive behavior (conditioned reinforcement and Pavlovian-to-instrumental transfer) is disrupted in cannabinoid receptor knockout mice (Crombag et al. SFN 2007). These results raise questions about the nature of the deficits in reward representation in CB1 knockout mice. Representations of a reward involve both sensory and motivational properties of reinforcement, and cues may form associations with both of these features of a reward. Here we used an outcome-specific devaluation procedure to examine whether the deficits previously observed after CB1 receptor deletion may be due to an inability to represent and/or use sensory-specific incentive motivational properties of reward. Homozygote (KO) and heterozygote (HET) CB1 mutant mice, together with wildtype (WT) controls, were trained to associate responding on one lever with one outcome (orange flavored sucrose) and responding on a second lever with a different, sensory specific outcome (grape flavored sucrose). Subsequently, the value of one of these outcomes was attenuated by selectively pre-feeding mice during a 2-hr period and the propensity of the mice to respond for the devalued and non-devalued outcome was assessed under extinction conditions. As expected, in WT mice, responding on the lever associated with the pre-fed outcome (i.e., the devalued outcome) was significantly lowered compared to responding on the lever associated with the non-devalued outcome. By contrast, CB1 KO and HET mice failed to suppress responding on the lever associated with the devalued outcome. Importantly, during a subsequent choice test we established that mice were able to discriminate between the devalued and non-devalued flavors directly, irrespective of genotype. These deficits mirror those seen after lesions of the basolateral amygdala or prefrontal cortex and suggest that CB1-mediated neurotransmission in this region is necessary for encoding relationships between sensory-specific features of food rewards and their incentive value.
Funded by NIH (P40RR017688)


Inducible inactivation of BDNF receptor TrkB impairs rate of discriminative eyeblink conditioning in mice
M.J. Schmidt¹, A.J. Sherwood¹, D.R. Smith¹, X. Chen², M.E. Stanton^1,3, D.D. Ginty^2
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;
²Howard Hughes Med. Institute, Dept. of Neurosci., Johns Hopkins Univ.
³Psychology, University of Delaware, Newark, DE.

Eyeblink conditioning is a powerful paradigm for studying the effects of specific genetic mutations on cerebellar function in mice (Chen, et al., 1996; Kato, et al., 2005; Weiss, et al., 2002; Woodruff-Pak, 2005). Qiao et al. (1998) reported a deficit in the acquisition of eyeblink conditioning in the stargazer mouse, a spontaneous mutant characterized by cerebellar anomalies, ataxia and generalized spike wave seizures, with reportedly low levels of BDNF expression in the cerebellum (Qiao, et al., 1996). To directly examine the contribution of BDNF and its receptor TrkB, the present study examined discriminative eyeblink conditioning in inducible knockin mice susceptible to TrkB inhibition by systemically injected 1NMPP1 (Chen et al., 2005). Furthermore, as most mouse eyeblink studies involve single-cue conditioning, the present study examines discrimination learning (two-cue conditioning) because this procedure offers a nonassociative control condition within the same subjects. TrkB-inhibited and non-inhibited control mice received 8 acquisition sessions of tone-light discrimination training (Paczkowski et al., 1999) using the following parameters: 1 session/day, 50 CS+ and 50 CS- trials/session, 380 msec 70 dB tone or 15 W light presented against dark background, US = 100 msec, 0.75 mA perioccular-shock, ISI=280 msec, alpha-response period = 0-40 ms after CS onset. Alpha- and unconditioned responses did not differ across groups. Although inhibited mice reached the same level of asymptotic conditioned responding as the non-inhibited controls by the end of training, the rate of acquisition for the inhibited mice was slower than controls, particularly in the CR amplitude measure. Our findings support a role of BDNF-TrkB signaling during the acquisition of eyeblink conditioning.
Funded by NIH (P40RR017688)


Comparison of three mouse strains in discrimination and reversal learning of the conditioned eyeblink response
A.J. Sherwood¹, M.J. Schmidt¹, D.R. Smith¹, M.E. Stanton^1,2
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;
²Psychology, University of Delaware, Newark, DE.

In discrimination and reversal of eyeblink conditioning, conditioned responses (CRs) are acquired to a conditioned stimulus (CS+) that is paired with the unconditioned stimulus (US), but not a second conditioned stimulus (CS-) that is presented alone. During reversal learning, in which the CS+ becomes the CS- and vice versa, CRs are acquired to the (new) CS+ and extinguish to the (new) CS-. Initial discriminative learning is cerebellar dependent (Kim & Thompson, 1997) whereas extinction of CRs during subsequent reversal learning also engages forebrain areas (Berger & Orr, 1983; Chachich & Powell, 1998). Here we present the results for three strains of mice tested on a discrimination and reversal eyeblink conditioning protocol. C57/BL6, 129/SvImJ and a hybrid of these two strains (F1) received 4 acquisition sessions of tone-light discrimination training followed by 8 reversal sessions (Stanton et al., 2007) using the following parameters: 1 session/day, 50 CS+ and 50 CS- trials/session, 380 msec 70 dB tone or 15 W light presented against dark background, US = 100 msec, 0.75 mA perioccular-shock, ISI=280 msec, alpha-response period = 0-40 ms after CS onset. All three strains showed robust discriminative eyeblink conditioning, with CRs to the CS+ reaching 80-90% by the 4th session, and levels of responding to the CS- remaining at ~40% throughout. During reversals only the C57 and F1 mice acquired CRs to the new CS+ (former CS-) reaching asymptotic levels of 90% CRs, vs. ~60% for the 129 mice. Extinction to the new CS- (former CS+) was modest in the C57 and F1 mice and somewhat greater in the 129 miceIt is likely that with additional reversal trials the C57 and F1 mice will show further extinction to the CS-, and this will be tested in future studies. Our results show that discrimination reversal can be used in studies of eyeblink conditioning in genetic mouse models to examine functional interactions between cerebellar circuitry and forebrain regions.
Funded by NIH (RR017688)


Normal Pavlovian modulation of appetitive responding is disrupted in cannabinoid receptor (CB1) knockout mice
H.S. Crombag¹, E. Galarce¹, A. Johnson¹, J. Johnson¹, A. Zimmer², A. Zimmer², P. Holland^1
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;
²Inst. of Mol. Psychiatry, Univ. of Bonn, Bonn, Germany

Overeating is rapidly becoming a major health concern in our society. Much benefit will be gained by identifying the psychological and neurobiological processes involved in normal and abnormal eating. Increasingly, learning and memory processes are being considered as studies have shown that learned cues can override adaptive regulatory mechanisms and alter food-procuring (appetitive) and consuming behavior. For instance, Pavlovian cues associated with food delivery can sustain or reinforce food-seeking behavior (conditioned reinforcement; CRf) and/or potentiate ongoing instrumental responding for food (Pavlovian-to-instrumental transfer; PIT). These effects of learned cues on appetitive behaviors depend on a relatively well characterized neural circuitry that includes regions of the amygdala and prefrontal cortex. The current experiments studied the role of cannabinoid (CB1) receptor in the effects of Pavlovian cues in CRf and PIT. Mice with a full (KO) or partial (HET) genetic knockout of the CB1 receptor, and littermate control mice (WT), were trained on a Pavlovian discrimination task to associate an auditory cue (CS+) with reward delivery (10% sucrose) and a second cue with the absence of reward (CS-). During the subsequent test for CRf, the ability of response-contingent presentations of the CS+ (and CS-) to reinforce acquisition of a new instrumental response was assessed. In the PIT study, mice underwent Pavlovian discrimination training as before and, on separate sessions, training to instrumentally respond (lever press) for the same reward. PIT was tested by presenting the CS+ during performance of the instrumental behavior. The following results are reported: In both experiments, CB1 receptor mutation did not alter Pavlovian discrimination learning. Performance during instrumental training was attenuated in CB1 KO and HET mice but this genotype difference was seen only when the behavioral demand (i.e., schedule of reinforcement) for reward delivery was increased. More important, both CRf and PIT were affected by CB1 mutation in that, 1) KO mice failed to respond more for the CS+ during the test for CRf, and, 2) both KO and HET mice failed to show potentiated responding during non-contingent CS+ presentations on the test for PIT. Our findings add to a growing literature identifying cannabinoid CB1 receptor as a potential therapeutic target for the treatment of eating disorders, as well as for non-food maladaptive disorders such as nicotine and cocaine addiction.
Funded by NIH (RR017688)


Evaluating the effects of cocaine exposure on goal-directed and habitual responding
D.R. Smith¹, H.S. Crombag¹, M. Gallagher¹, P.C. Holland¹, A. Sherwood¹, A.W. Johnson^1
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;

According to the DSM-IV a defining characteristic of drug addiction is the individual’s failure to abstain from using the substance despite having evidence of the difficulty it is causing. Although initial drug use can be characterized as a goal-directed process, after a prolonged drug-taking history the addict’s behavior becomes dominated by a maladaptive habitual process in which drug-taking continues despite knowledge of the adverse consequences associated with those actions. It is possible to model the transition from goal-directed to goal-independent behavior using tests of instrumental reinforcer devaluation. In this paradigm, subjects are trained to perform two separate instrumental responses, each leading to a specific outcome. After training, one of the outcomes is devalued by prefeeding the reinforcer prior to conducting the test under extinction conditions. Typically, subjects who respond in a goal-directed manner prefer the response whose reinforcer was not previously devalued. By contrast, subjects responding in a goal-independent habitual manner fail to show this sensitivity to post-conditioning changes in reinforcer value. In the present experiments, mice were pre-treated with cocaine (30 mg/kg) or saline for 10 sessions either prior to (Experiment 1) or following (Experiment 2) instrumental training. Subsequently, mice were pre-fed with one of the two reinforcers prior to an assessment of responding. As expected, mice treated with saline responded in a goal-directed manner, favoring the response trained with the non-devalued reinforcer. However, cocaine treatment resulted in habitual responding, whereby mice were unable to shift responding based on changes in reinforcer value. Importantly, both groups of mice consumed more of the non-devalued reinforcer in a subsequent reinforcer choice test, indicating that performance in the instrumental response test could not be accounted for by a failure to discriminate between the reinforcers themselves or a failure of the devaluation treatment. Collectively, these results mimic that seen following orbitofrontal-amygdalar damage and indicate that cocaine exposure results in habitual responding, paralleling the persistent drug-taking despite adverse consequences seen in cocaine addicts.
Funded by NIH (P40RR017688)


The role of neuronal activity regulated pentraxin (narp) in motivational learning
I.M. Reti¹, H.S. Crombag¹, J. Sutton⁴, A.W. Johnson², J. Johnston², K. Takamiya³, R. Huganir³, J.M. Baraban¹, M. Gallagher², P.C. Holland^2
1Dept. Psychiatry, Johns Hopkins University, Baltimore, MD;
²Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;
³Dept. of Neuroscience, Johns Hopkins University, Baltimore, MD;
⁴University of Cincinnati, OH;

Neuronal activity regulated pentraxin (NARP) is a secreted immediate early gene product regulated by synaptic activity. Recent studies have shown it plays a key role in excitatory synaptogenesis by regulating AMPA receptors at the synapse. As AMPA receptors mediate synaptic plasticity and learning, and as Narp is selectively expressed in amygdala and lateral hypothalamus, we investigated Narp’s role in motivational learning. Specifically, we examined whether mice lacking NARP were capable of learning a simple cue-reward discrimination, and whether such cues were able to influence motivated behavior. Mice were trained to discriminate between presentations of a reward-paired auditory cue (CS+) and an unpaired auditory CS-. Both NARP knock-out (KO) and littermate control mice (WT) acquired the Pavlovian discrimination. During subsequent testing phases the reward-paired CS+ was capable of augmenting ongoing instrumental performance (Pavlovian-to-instrumental transfer) and was capable of supporting the acquisition of novel instrumental nose-poke responding (conditioned reinforcement). These results suggest that NARP is not involved in mediating general motivational effects of rewarded cues on learning and performance. However, the results of an additional experiment implicate NARP in using sensory-specific features of expected reward value to direct instrumental performance. Using an outcome-specific devaluation paradigm, mice were trained to respond on one lever for one reward (e.g., grape-flavored sucrose) and respond on a second lever for a different reward (e.g., orange-flavored sucrose). Following training, mice were pre-fed with one of the two rewards for a 2-hr period. This sensory-specific satiety treatment served to devalue one reward, while maintaining the value of the other reward. Responding to both levers was then assessed in an extinction test. As expected, WT control mice showed a significant preference in responding to the lever associated with the non-devalued reward. In contrast, NARP KO mice responded equally to both levers, failing to suppress responding to the lever associated with the devalued reward. Both groups of mice consumed more of the non-devalued reward in a subsequent reward choice test, indicating that performance in the instrumental response test could not be accounted for by a failure to discriminate between the rewards themselves or a failure of the devaluation treatment. Collectively, these results suggest that NARP-mediated neurotransmission has a selective role in encoding sensory-specific motivational value, but not the general motivational effects of rewarded cues on performance.
Funded by NIH (P40RR017688 & DA016303)


>Narp mediates retention of emotional memories
J.M. Baraban¹, H.S. Crombag³, M. Dickson¹, M. DiNenna³, P.C. Holland³, I.M. Reti^2
1Dept. of Neuroscience, Johns Hopkins University, Baltimore, MD;
²Dept. Psychiatry, Johns Hopkins University, Baltimore, MD;
³Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;

The lateral hypothalamus is a key brain region implicated in reward and motivation. In recent years the orexin neurons have been identified in this region as important mediators of both food and drug rewarding behaviors, for example, conditioned place preference to morphine. In prior studies we have shown that orexin neurons selectively express Narp, a secreted protein which regulates AMPA receptors at synapses and which plays a role in maintaining memory traces induced by aversive stimuli. To test if Narp also mediates rewarding behavior we have assessed if Narp KO mice display morphine place preference using a single-chamber, unbiased design. We found that Narp KO mice acquire morphine place preference at least as well as WT control mice. To check how well this memory is retained, we attempted to extinguish preference for the conditioned side by daily administering a saline injection and then exposing mice to the conditioning chamber. Whilst control mice showed no preference for the morphine-paired side after 13 extinction trials, the Narp KO mice extinguish at a slower rate, failing to extinguish preference for the morphine paired side after an additional 10 trials. Together with our previous findings, these results suggest Narp plays a key role in regulating retention of rewarding as well as aversive memories. Future studies are aimed at determining whether this phenotype is caused by Narp deletion from the orexin cells or from another brain region and what the molecular mechanism are underlying the phenotype.
Funded by NIH (RR017688 & DA016303 & P50DA000266)


Effects of cues associated with surprising meal interruption on food consumption in mice
M.A. McDannald¹, E.M. Galarce¹, J. Johnson¹, H.S. Crombag¹, P.C. Holland^1
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;

Food consumption is controlled by both internal and external factors. Environmental signals associated with food may prepare an animal to forage, consume and digest more effectively. Furthermore, environmental cues that provide information about food availability enable animals to make predictions about future food resources and act upon that knowledge in appropriate fashion. For example, when exposed to a cue that signals the presence of food, an animal experiencing, or having experienced, hunger can eat beyond its present needs to cope with predicted future famine. Interestingly, cues paired with meal interruption have a similar effect. That is, cues previously paired with surprising meal terminations can increase food consumption later. Here, using a novel Pavlovian conditioning procedure, food-deprived mice learned to associate a conditioned stimulus with an unexpected termination of a food trial. Subsequently, when experimental food was made available, sated mice consumed more food in the presence of these cues than when exposed to cues that were paired with food, or in the absence of any discrete food-related signals.
Funded by NIH (RR017688)

Society for Neuroscience Conference 2006

As Narp is an immediate early gene implicated in regulating AMPA receptor trafficking, it is thought to play a key role in behavioral plasticity. In previous studies, we have found that Narp is induced in the central nucleus of the amygdala, the BNST and the nucleus accumbens by opiate withdrawal. As these regions mediate the long-lasting aversive responses to opiate withdrawal, we have examined whether Narp KO mice display abnormalities in this behavioral paradigm. Narp KO and wild type mice were made opiate-dependent by implantation of morphine pumps (4mg/kg/hr). Naltrexone 250 micrograms/kg was used to trigger opiate withdrawal. Scoring of multiple somatic signs of opiate withdrawal did not reveal an effect of genotype during the acute withdrawal phase. Conditioned place aversion was tested on day 7 after conditioning and acquisition of this behavior was similar in Narp KO and WT mice. However, when mice underwent active extinction training, we noted that Narp KO mice displayed more rapid extinction of this behavior. In the absence of active extinction, the aversive response was sustained for four weeks, indicating that Narp is not needed for maintaining this behavior. Thus, these studies suggest that Narp plays a key role in aspects of synaptic plasticity that are critical for generating stable behavioral responses that are resistant to extinction. As the persistence of aversive responses to opiate withdrawal have been postulated to contribute to opiate addiction, these findings indicate that suppression of Narp induction or function may decrease craving for opiates or may enhance the efficacy of extinction based behavioral interventions.
Funded by NIH (DA016303, DA000266, & P40RR017688)


Discriminative Eyeblink Conditioning in Three Mouse Strains
M.J. Schmidt¹, A.J. Sherwood¹, D.R. Smith¹, M.E. Stanton^2
1Neurogenetics and Behavior Center, Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD;
²Psychology, University of Delaware, Newark, DE.

Studies of eyeblink conditioning in the mouse are expanding rapidly because they provide an opportunity to use gene-targeting techniques to examine the molecular mechanisms of neural plasticity and behavioral learning in relation to defined cerebellar circuitry and interactions of forebrain regions with this circuitry (e.g., Kishimoto et al., 2006).  Most of this work has involved single-cue conditioning (delay or trace conditioning) in C57/B6 mice.  The present study examines discrimination learning because this procedure offers a nonassociative control condition and a probe of cerebellar (acquisition) and forebrain (reversal) substrates of learning, all within the same subjects.  Strain differences are important in behavioral genetics and have been examined to some extent in single-cue eyeblink conditioning (Bao, Chen & Thompson, 1998).  The present study examined strain differences in discriminative eyeblink conditioning.  C57/BL6, 129/SvImJ and a hybrid cross of these two strains (F1) received 8 acquisition sessions of tone-light discrimination training (Paczkowski et al., 1999) using the following parameters: 1 session/day, 50 CS+ and 50 CS- trials/session, 380 msec 70 dB tone or 15 W light presented against dark background, US = 100 msec, 0.75 mA perioccular-shock, ISI=280 msec, alpha-response period = 0-40 ms after CS onset).  All three strains showed robust discriminative eyeblink conditioning.  Within about 4 daily sessions, asymptotic levels of responding were reached to both CS+ (70-80 %CRs) and CS- (~30 %CR, after a transient increase above this level). All strains showed components of CR amplitude on CS-alone probe trials that peaked around the time of US onset on paired trials, although CR topographies differed across strains. The advantages for neurogenetics of applying discriminative eyeblink conditioning across a range of genetic backgrounds are discussed. 

Funded by NIH (RR017688).

Society for Neuroscience Conference 2005

Appetitive Pavlovian conditioned stimuli can exert motivational influences on goal-directed behavior. For example, stimuli associated with primary rewards can enhance instrumental responding for that reward (Pavlovian-to-instrumental transfer [PIT]), and support acquisition of novel instrumental responding (conditioned reinforcement [CRf]). These two manifestations of Pavlovian-instrumental interactions are dissociable neurobiologically. For instance, mice lacking the GluR1 or GluR2 subunit of AMPA receptor show selective deficits in CRf and PIT, respectively (Mead & Stephens 2003). To further explore the role of GluR1 in reward learning we examined PIT and CRf in mice lacking the S845 phosphorylation site of the AMPA-GluR1 subunit. First, S845 mutant and WT mice were trained to associate an auditory cue (CS+) with milk reward and in separate sessions to lever press for the same reward. Once accurate and stable responding was established mice were tested for PIT by presenting the CS+ during instrumental responding, but under extinction conditions. To assess CRf, mice were trained to associate a 10 sec auditory cue with reward and a single session was conducted to determine the ability of the cue to support acquisition of a new instrumental response. We report that 1) no genotype differences were seen during Pavlovian or instrumental training sessions; 2) CS+ presentation significantly elevated (by ~200%) instrumental responding over baseline levels but no genotype differences were evident in the magnitude of PIT; 3) CS+ reinforced instrumental responding was significantly elevated relative to baseline (non-reinforced) levels but, again, no genotype differences were seen in CRf. We conclude that the AMPA receptor GluR1-S845 site, phosphorylated by cAMP-dependent protein kinase (PKA), is not necessary for normal reward learning to occur and for Pavlovian cues to influence instrumental behavior.

National Center for Research Resources Conference 2006

We have refined and optimized several widely used behavioral protocols for the evaluation of mice using strains of various genetic backgrounds.