Lesions of the subthalamic nucleus (STN) alleviate the cardinal signs of idiopathic as well as MPTP-induced Parkinson's disease in primates. For this reason, the STN is a target for clinical treatment of Parkinson's disease using deep brain stimulation. Despite its small size, the STN plays a vital role in the cortico-basal ganglia-thalamic network. However, the functional features of the STN have yet to be fully uncovered. The research presented in this thesis examines the functions of the STN by measuring behavioural changes resulting from STN lesions in rats performing executive abilities. In the first experiment, a ‘signal change' reaction time task was developed and the performance of humans and rats was compared. The main findings were that although humans and rats used different strategies in the task, the task did challenge the ability to inhibit unwanted responses. In the second and third experiments, the effects of bilateral lesions of the STN on performance of two variants of the ‘signal change' task were examined. Rats with the STN lesions were able to inhibit responses when under stimulus control, but were less able to inhibit responses that were not under stimulus control. In the final experiment, the effects of lesions of the STN on inhibitory control in a nonmotor, cognitive domain were examined. Rats with STN lesions were not impaired on reversal learning, suggesting intact inhibition of previously rewarded responses. The rats with STN lesions did show impairments in selective attention which resulted in an inability to form an attentional set. Together, these findings challenge the conventional view that the STN simply plays a global inhibitory role. Rather, the contribution of the STN to inhibitory control is more complex and neither the motor nor the cognitive effects of the lesions are easily explained simply as a failure of inhibition.

Whether there are sex differences in the kinematic organization of non-reproductive behaviors is rarely addressed. In this thesis, evidence is presented that male and female rats organize their posture and stepping differently during a food protection task, contact righting, skilled reaching, and vertical rearing. Neonatal gonadal steroid exposure can alter sex-typical patterns of movement organization. Whether these differences are due to sex differences in body morphology or central nervous system (CNS) was also addressed using gravid females and tfm males. The results reveal that sex differences in movement are CNS based. Furthermore, the expression and choice of sex-typical patterns of movement can be altered by CNS injury. Finally, evidence is presented that sex differences in movement organization are also present in marsupials and insects. The implications of these results for our understanding of the evolution of sex differences in CNS anatomy and behavior will be discussed. / xvi, 249 leaves : ill. ; 28 cm.

The behavioural and electrophysiological consequences of two newly developed aniracetam analogues were investigated in male Long-Evans rats. Results indicate that an intraperitoneal (i.p.) injection of LD38.2 significantly improved retention in a two odour olfactory discrimination task. However, three different dosages of LN1 did not facilitate memory in the task. In rats with chronically implanted electrodes, both compounds rapidly crossed the blood brain barrier (BBB) after an i.p. injection and influenced several parameters of the field excitatory postsynaptic potential (EPSP) in the CA1 and dentate gyrus regions of the hippocampus. The enhancement of the field EPSP following LD38.2 administration may be related to the drug's ability to facilitate memory in the olfactory discrimination task. Compounds, like LD38.2, that enhance both hippocampal transmission and performance in learning/memory tasks in laboratory rodents may have implications for the treatment of clinical memory disorders.

The hippocampus is necessary for normal memory in rodents, birds, monkeys, and people. Damage to the hippocampus can result in the inability to learn new facts, defined by the relationship among stimuli. In rodents, spatial learning involves learning about the relationships among stimuli, and exemplifies the kind of learning the requires the hippocampus. Therefore, understanding the neural mechanisms underlying spatial learning may elucidate basic memory processes. Many hippocampal neurons fire when behaving rats, cats, or monkeys are in circumscribed regions (place fields) of an environment. The neurons, called place cells, fire in relation to distal stimuli, but can persist in signaling location when the stimuli are removed or lights are turned off (memory fields). In this thesis, computational models of spatial information processing simulated many of the defining properties of hippocampal place cells, including memory fields. Furthermore, the models suggested a neurally plausible mechanism of goal directed spatial navigation which involved the encoding of distances in the connections between place cells. To navigate using memory fields, the models required an excitatory, distributed, and plastic association system among place cells. Such properties are well characterized in area CA3 of the hippocampus. In this thesis, a new electrophysiological study provides evidence that a second system in the dentate gyrus has similar properties. Thus, two circuits in the hippocampus meet the requirements of the models. Some predictions of the models were then tested in a single-unit recording experiment in behaving rats. Place fields were more likely to occur in information rich areas of the environment, and removal of single cues altered place fields in a way consistent with the distance encoding mechanism suggested by the models. It was concluded that a distance encoding theory of rat spatial navigation has much descriptive and predictive utility, but most of its predic

When given a choice between getting a high reward that requires climbing a high ramp or pressing a lever multiple times, versus freely obtaining a low reward, healthy rats prefer the former, while rats with lesions to the anterior cingulate cortex (ACC) prefer the latter. We developed two novel effort tasks to examine if ACC mediates other types of physical effort (weight-lifting) as well as emotional effort (courage). We replicated previous findings on a modified version of the ramp-climbing task, showing that ACC lesions impair these decisions. Lesions of ACC did not impair weight-lifting effort, even when higher levels of effort were used and training on the task was eliminated. Initially, lesions of ACC did not impair courage effort. When the task effort was subsequently increased, rats with ACC lesions showed a failure to adapt to novelty throughout testing. This research indicated that not all effort is mediated by ACC. / xii, 177 leaves : ill. ; 29 cm

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The influence of play behavior on the brain was investigated through plasticity and metaplasticity methodology. Regions in both cortical and sub-cortical areas were investigated. Animals in both studies either experienced play with juvenile partners or did not experience play by being paired with an adult. Play experience alone was shown to affect the plasticity in the prefrontal cortex, although it did not show structural changes to sub-cortical regions. If animals were given nicotine after play experiences, the affects of play in the prefrontal cortex were abolished. In addition, playful behaviors appear to prime some sub-cortical regions of the brain for expression of later plasticity. Thus, play appears to alter the structure of multiple brain areas, but do so in different ways. / ix, 67 leaves ; 29 cm

Indiana University-Purdue University Indianapolis (IUPUI) / Naltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a non-selective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to delta and kappa receptors. Like the mu system, the delta receptor system has also been implicated in mediating the rewarding effects of EtOH. In contrast, the role of the kappa system is less clear though recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of both mu-selective and non-selective doses of naltrexone, the selective delta antagonist naltrindole (NTI), and the selective kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek versus consume a reinforcer to assess whether these receptor-selective drugs differentially affects these behaviors in both selected (alcohol-preferring P rats) and non-selected (Long Evans) rats, and whether these effects are specific to EtOH. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either vehicle or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), NTI (IP; 2.5, 5.0, or 10.0 mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 20 (U50), 15 (NTI), or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall: U50, NTI, and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats reinforced with EtOH were more sensitive to NTI’s effects on intake and seeking than all other rat groups. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa, delta, and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake.

Indiana University-Purdue University Indianapolis (IUPUI) / Differences in voluntary consumption of ethanol have been negatively correlated with differences in initial sensitivity and tolerance to ethanol’s pharmacological effects. From this perspective, both adolescent and adult alcohol-nonpreferring (NP) rats would be expected to be initially more sensitive to the sedative and hypothermic effects of ethanol and fail to acquire tolerance to those effects than preferring (P) rats. The first objective of this experiment was to assess alcohol-induced hypothermia and locomotor sedation in adolescent and adult P and NP rats over five consecutive daily administrations (saline, 1.5 g/kg, or 3.0 g/kg ethanol 17%v/v), testing the hypothesis that the P rats would acquire tolerance to the hypothermic response whereas the NP rats would not show changes across days. In addition, it was hypothesized that there would be age-related differences in initial sensitivity to ethanol, evident by adolescent rats displaying less ethanol-induced hypothermia and locomotor sedation than adult rats on Day 1. The second objective was to determine if conditioning was occurring between the administration environment and the hypothermic response and locomotor sedation elicited by ethanol exposure, via a sixth injection of saline. Female rats were surgically implanted with intraperitoneal Mini Mitter telemetry probes on postnatal day 25 or 85 and experimental manipulations began five days later. Data were collected every minute; temperature data were then converted to change from baseline scores and locomotor data were totaled for each session. On Day 1, maximum temperature reduction elicited by the 3.0 g/kg dose was greater in the NP rats than the P rats, regardless of age. That dose also produced greater levels of locomotor sedation in the adult rats compared to the adolescent rats, regardless of line. The 1.5 g/kg dose of ethanol produced a greater hypothermic response in adult rats compared to adolescent rats, locomotor activity was reduced equally across the groups. With repeated administrations, NP adult rats displayed sensitization to the hypothermic response elicited from the 3.0 g/kg dose; in contrast, tolerance to the hypothermic response was found within the 1.5 g/kg dose for the adolescent P, adult P, and the adult NP rats. Repeated saline administrations also resulted in tolerance to the hypothermic response associated with administration in the adult NP and adolescent P rats. On the Day 6 saline administrations, adult rats which had previously been exposed to the 3.0 g/kg dose, maintained their baseline body temperatures better than both of the other exposure groups. Adolescent rats failed to show any signs of conditioning when administered saline on Day 6. Contrary to prediction the P rats failed to acquire tolerance to the 3.0 g/kg dose for either measure; and the line difference in ethanol-induce hypothermia was due to sensitization of the hypothermic response in adult NP rats. These results also provide further support that adolescent rats are less sensitive to the initial aversive effects of ethanol at the 1.5 g/kg dose for ethanol-induced hypothermia and the 3.0 g/kg dose for locomotor activity. The current experiment provides evidence that initial sensitivity as well as the acquisition of tolerance to ethanol-induced hypothermia may be behavioral phenotypes correlated with selection for high and low alcohol drinking preference.