Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion.

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown. In the present study, we compared voluntary ethanol consumption and self-administration, yohimbine-induced reinstatement of ethanol seeking, and ethanol-induced conditioned taste aversion in rats with sham or LHb lesions. In rats given home cage access to 20% ethanol in an intermittent access two bottle choice paradigm, lesioned animals escalated their voluntary ethanol consumption more rapidly than sham-lesioned control animals and maintained higher stable rates of voluntary ethanol intake. Similarly, lesioned animals exhibited higher rates of responding for ethanol in operant self-administration sessions. In addition, LHb lesion blocked yohimbine-induced reinstatement of ethanol seeking after extinction. Finally, LHb lesion significantly attenuated an ethanol-induced conditioned taste aversion. Our results demonstrate an important role for the LHb in multiple facets of ethanol-directed behavior, and further suggest that the LHb may contribute to ethanol-directed behaviors by mediating learning driven by the aversive effects of the drug.

Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine.

RATIONALE: Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized. OBJECTIVE: To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a ß antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist). METHODS: Sprague-Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays). RESULTS: Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice. CONCLUSIONS: The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior.

Activation and survival of immature neurons in the dentate gyrus with spatial memory is dependent on time of exposure to spatial learning and age of cells at examination.

Neurogenesis continues to occur throughout life in the dentate gyrus of the hippocampus and may be related to hippocampus-dependent learning. We have recently reported that there is an enhancement of neurogenesis in the hippocampus only when BrdU is administered 6 days prior to starting spatial training but not when training started either 1 day or 11 days following BrdU administration. In that study, all rats were perfused on day 16 after BrdU injection in order to compare cells of the same age (i.e. 16 day old cells) and thus the survival time after learning was different between groups. This study was designed to address whether the amount of time that passed following training could also contribute to the effects of spatial learning on hippocampal neurogenesis and whether there was differential new neuron activation in response to spatial learning that depended on the age of new cells at the time of spatial learning. Here we tested whether a survival period of 5 days following spatial learning at either 1-5, 6-10 or 11-15 days following BrdU administration would alter cell survival and/or activation of new neurons. Our results indicate that 5 days after training in the Morris water task cell survival is unaltered by training on days 1-5, increased by training at days 6-10 and decreased when training occurs on days 11-15. Furthermore spatial learners trained on days 6-10 or 11-15 show greater activation of new neurons compared to cue-trained rats during a probe trial 5 days after training. In addition, rats trained on the spatial task on days 11-15 had a greater number of activated new neurons compared to rats trained on the spatial task on days 6-10. These results suggest there is a gradual removal of older BrdU-labeled new neurons following spatial learning perhaps due to a competitive interaction with a population of younger BrdU-labeled new neurons.

Effects of zona incerta lesions on striatal neurochemistry and behavioral asymmetry in 6-hydroxydopamine-lesioned rats.

Analysis of optimal sites for neurosurgical interventions in patients with Parkinson's disease (PD) suggests that significant clinical benefits may be achieved by involvement of the zona incerta (ZI). Unilateral electrolytic ZI lesions were made in intact and ipsilaterally 6-hydroxydopamine (6OHDA)-lesioned rats. Extracellular levels of glutamate, dopamine, and its metabolites in the ipsilateral striatum of awake rats were measured by using microdialysis, and tests of behavioral asymmetry were performed. In intact rats, ZI lesions had no effect on striatal extracellular glutamate or absolute levels of dopamine or metabolites, but dopamine metabolism decreased. After ZI lesions, contralateral forepaw use decreased in the forepaw adjusting steps test, but there was no change in response to vibrissa stimulation or cylinder exploration. There was no development of rotational asymmetry with amphetamine. In 6OHDA-lesioned rats, striatal extracellular glutamate levels were elevated compared with controls. ZI lesions reduced the increased levels of glutamate back to normal values. ZI lesions reduced dopamine and homovanillic acid levels and showed a trend toward a decrease in dopamine metabolism. 6OHDA-lesioned rats demonstrated the expected asymmetry of motor behaviors. After ZI lesions, ipsilateral turns following amphetamine injection were reduced, and there was a trend toward improved symmetry of forepaw use as determined with the forepaw adjusting steps test. There was no change in forepaw use with vibrissa stimulation or cylinder exploration. These data indicate that lesions of the ZI can affect striatal neurochemistry and motor behavioral asymmetry and suggest potential mechanisms by which ZI lesions may improve symptoms in PD.

Task difficulty in the Morris water task influences the survival of new neurons in the dentate gyrus.

Adult neurogenesis continues throughout life in the mammalian hippocampus. The precise function of the adult generated neurons remains uncertain although there is growing evidence that they are involved in hippocampus-dependent learning and memory. Training rats on a hidden platform version of the Morris water task has been shown to increase or decrease the survival of newly produced cells in the dentate gyrus (DG) compared to training on a visible platform version. Here we investigated whether the difficulty of the task is related to the degree or direction of the change in neurogenesis. We trained rats on either a visible platform version of the Morris water task or one of three different hidden platform paradigms: four training trials per session version, two training trials per session, and reduced-cue (a version in which the majority of the distal cues were removed from the room). BrdU was administered 6 days prior to training and rats were perfused 24 h after the last training session. As expected, training on the four trial hidden platform version increased cell survival compared to training on the visible platform version. However, training on the more difficult reduced-cue hidden platform version resulted in a decrease in cell survival. Rats that received fewer trials per session did not differ in terms of cell survival in comparison to rats trained on the visible platform version. These findings demonstrate that altering the difficulty of the spatial task has an impact on the corresponding change in cell survival. The lack of obvious distal cues likely changed the strategy used by the rats to determine the location of the platform and resulted in a decrease, instead of an increase in cell survival in the hippocampus. In conclusion, different types of hippocampus-dependent learning can differentially impact cell survival.