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This research examines the hypothesis that the satiety effect of cholecystokinin octapeptide (CCK-8) is mediated by changes in gastric emptying. A method for collection of gastric emptying data, the double sampling procedure, is developed and validated for use in the rat. The double sampling technique permits repeated measurements of liquid gastric volume and thus describes the time course of emptying within a single experimental session. Further, the method allows determination of the amount of gastric secretion, volume emptied into the intestines, and amount of gastric load remaining in the stomach. Experiments are presented which: i) demonstrate the utility of the technique; ii) validate its accuracy in determining gastric volume; iii) indicate the stability of measurements obtained with this procedure; and iv) provide a procedure for quantitative evaluation of data obtained with this technique. Using the double sampling procedure, the ability of CCK-8 to delay gastric emptying and to influence feeding are then compared under similar experimental conditions. The effect of CCK-8 on gastric emptying is assessed in 6 hr deprived rats receiving 10 ml intragastric test loads of either .15M saline or 15% sucrose. Intraperitoneal (ip) injections of CCK-8 in doses of 1.4-22.4 ug/kg produce a dose-dependent retardation of gastric emptying of both saline and nutrient. Lower doses of CCK-8, 0.01 and 0.1 ug/kg, have no effect on gastric emptying. The effect of CCK-8 on feeding is assessed in rats tested under the same experimental conditions used in the gastric emptying studies. Doses of CCK-8 capable of retarding gastric emptying also suppress eating in a dose-dependent manner. These findings provide necessary correlational support for the hypothesis that satiety produced by CCK-8 is mediated by inhibition of gastric emptying. However, a further quantitative analysis of the correspondence of the gastric emptying and feeding effects of CCK-8 suggest that retardation of emptying may not account for the entire satiety effect of the peptide. The next set of studies provide direct tests of whether changes in gastric emptying mediate CCK-induced satiety. If gastric emptying plays a significant role in the satiety produced by CCK-8 then: i) the effects of CCK-8 on emptying and feeding should share similar kinetics, and ii) peptides that inhibit emptying should also inhibit feeding. I show that CCK-8 (5.6 ug/kg) injected coincident with introduction of an intragastric load or presentation of a test meal produces a rapid inhibition of both emptying and feeding. In contrast, the identical dose of CCK-8 administered 15 min before testing causes no inhibition of emptying, even though the peptide retains its ability to produce satiety. I also test the abilities of the peptides pentagastrin (100 ug/kg), bombesin (8 & 16 ug/kg) and secretin (2.86, 14.3 & 28.6 ug/kg) to reduce food intake and inhibit gastric emptying. Pentagastrin does not affect food intake or gastric emptying. Bombesin causes a small transient delay in emptying but a large and sustained suppression of eating. High dose secretin (14.3 ug/kg) causes no significant reduction of food intake, even though this dose of secretin inhibits emptying to the same degree as 1.4 ug/kg CCK-8, which does reduce intake. Thus, although CCK-8 does influence the rate of gastric emptying, the present results indicate that the inhibition of emptying by CCK is neither necessary nor sufficient to explain its satiety effect. / Thesis / Doctor of Philosophy (PhD)

An observer rat that interacts with a conspecific, a demonstrator that has eaten a flavoured food, is subsequently more likely to eat that food than an alternative, novel food (Galef & Wigmore, 1983). In the first part of this thesis, four experiments were undertaken to determine the influence of unreliable demonstrators on observer food preference. In the first three experiments, observers were poisoned after interaction with demonstrators; a demonstrator that demonstrated a food that led to poisoning was considered an unreliable demonstrator. The first experiment compared the influence of an unreliable demonstrator and an unfamiliar demonstrator on observers' food preferences. Experiment 2 compared the influence of demonstration from an unreliable conspecific and a familiar conspecific that had only provided irrelevant information. The third experiment compared the influence of an unreliable and a reliable demonstrator. Experiment 4 compared the influence for protein-deficient observers of a demonstrator that had previously demonstrated a protein-deficient diet and a demonstrator that was unfamiliar. None of the first four experiments showed a significant difference in effectiveness of social transmission due to demonstrator quality. In the second part of the thesis I investigated the influence of familiarity on demonstrator effectiveness. In Experiment 5, the influence of local sisters was compared with that of unfamiliar non-relatives as demonstrators. Sisters were not better demonstrators than unfamiliar non-relatives. / Thesis / Master of Science (MSc)

Uncoupling protein, a mitochondrial inner membrane protein found in mammalian brown adipose tissue, functions as an uncoupler of oxidative phosphorylation by serving as a proton carrier when activated, resulting in heat production, the function of the tissue. Unlike most nuclear-encoded mitochondrial proteins, uncoupling protein is not made with a cleavable presequence. With the availability of an uncoupling protein cDNA clone, the region responsible for targeting uncoupling protein to mitochondria was examined using in vitro transcription and translation and import into isolated mitochondria. In order to localize the targeting sequence of uncoupling protein, fusion proteins containing portions of uncoupling protein and uncoupling protein modified by site-directed mutagenesis were constructed and analysed for their ability to be imported. Previously it has been shown that there was a targeting signal within uncoupling protein amino acids 13 to 105 (Liu et al., 1988). However, amino acids 13 to 51 did not target a passenger protein to mitochondria (Liu et al., 1988). Here the role of amino acids 53 to 105 of uncoupling protein in targeting was examined with two new constructs, uncoupling protein amino acids 53 to 105 joined to rat ornithine carbamoyltransferase amino acids 147 to 354 and to mouse dihydrofolate reductase. These two constructs along with uncoupling protein with amino acids 2 to 51 deleted were imported into mitochondria consistent with uncoupling protein amino acids 53 to 105 having a potential targeting role in uncoupling protein. Further, these three constructs were processed upon import. The major processed forms of all three constructs are approximately 20 amino acids smaller than the initial translation product. Both fusion constructs also have an intermediate-sized processed form approximately 14 amino acids smaller than the initial translation product. Processing suggests that at least the amino terminus of these proteins has reached the mitochondrial matrix. The location of the proteins was examined using Na2CO3 extraction. Uncoupling protein and U13-105-OCT (uncoupling protein amino acids 13 to 105 joined to ornithine carbamoyltransferase amino acids 147 to 354) were found in the membrane fraction while the processed forms of Ud2-51 (uncoupling protein with amino acids 2 to 52 deleted) and U53-105-DHFR (uncoupling protein amino acids 53 to 105 joined to dihydrofolate reductase) were found in the aqueous fraction suggesting that uncoupling protein amino acids 2 to 52/53 are involved in membrane localization. Analysis of Ud2-35 (uncoupling protein with amino acids 2 to 35 deleted) revealed that it was associated with both the membrane and aqueous fractions. Analysis of uncoupling protein amino acids 53 to 105 revealed the potential existence of two positively charged amphipathic a-helices. Based on the sizes of processed forms and on the helical wheel projection for the first possible sequence, arginine54 , lysine56 and lysine67 were changed to glutamines, individually and in various combinations using oligonucleotide site-directed mutagenesis. All mutant proteins were imported into mitochondria even when all three basic amino acids were replaced. The results suggest that this portion of uncoupling protein, amino acids 54 to 67, is not a targeting signal in the protein. / Thesis / Master of Science (MS)

Animals with one of septal, medial thalamic or tegmental reticular formation lesions were compared on three measures of spontaneous activity (a brief test in a novel maze and seven-day tests in running wheels or photocells cages) and on active avoidance learning. Wheel running was depressed by all the lesions (especially septal and tegmental lesions) while locomotion in the maze and photocell cages was unaffected. Avoidance learning was depressed by septal and thalamic lesions but not by tegmental lesions. These results are discussed in terms of the hypothesis that these brain structures form part of systems which facilitate or inhibit somatomotor activity. / Thesis / Master of Arts (MA)

Thesis advisor: Michael A. McDannald / The ability to appropriately respond to threats is critical for survival. Disruptions in the neural circuits underlying threat responding are studied in animal models and have clinical implications for anxiety disorders in humans. Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems for threat in animals. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is linked to imminent or occurring predation. Yet, the full neural circuit for conditioned, activity-promoting behaviors (e.g. locomotion, jumping, and rearing) remains unclear. The overarching goal of this dissertation is to demonstrate that a fear conditioned cue elicits a variety of defensive behaviors and to probe the neural circuit responsible for the expression of such activity-promoting defensive behaviors. To address the lack of research on activity-promoting defensive behaviors, I conducted experiments to observe multiple behaviors during fear discrimination over a baseline of reward seeking and constructed temporal ethograms of behavior. To improve efficiency in behavior scoring for future projects, I devised and trained a machine learning pipeline using convolutional neural networks. To aid in the understanding of the full neural circuit for activity-promoting defensive behaviors, I investigated the role of dopaminergic neurons of the ventral tegmental area in the expression of the defensive behaviors we observed during fear discrimination. Ultimately, the findings in this dissertation contribute to our general understanding of fear behavior in animals and may inform therapeutic strategies for anxiety disorders. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology and Neuroscience.

Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment. The non-competitive NMDA receptor antagonist, phencyclidine (PCP), is a psychomotor stimulant drug that has been shown to induce symptoms characteristic of schizophrenia in humans and animals. The aim of these studies was to use the sub-chronic PCP model in rats to investigate cognitive dysfunction in behavioural tests which have been highlighted as relevance by the MATRICS initiative (MATRICS.ucla.edu). The main tests used were attentional set-shifting, operant reversal learning, and novel object recognition tasks. The pharmacology of antipsychotics was studied in the reversal learning task using receptor selective compounds. Following this, experiments were carried out using in vitro electrophysiology and in vivo microdialysis in an attempt to investigate the mechanisms underpinning the PCP-induced cognitive deficits. The attentional set-shifting task is a test of executive function, the extra-dimensional shift (EDS) phase relates to the ability to shift attention to a different stimulus dimension; this is impaired in patients with schizophrenia. The studies presented in chapter 2 showed that sub-chronic PCP administration impaired attentional set-shifting performance selectively in the EDS phase, a deficit which was significantly attenuated by sub-chronic administration of clozapine and risperidone, but not haloperidol. The effect of PCP was also shown to be more robust in female rats compared to males. A deficit in set-shifting ability was also observed in isolation reared rats. However, the deficits produced by PCP were more robust than the deficit produced by isolation rearing. The reversal learning task is another test of executive function. Chapter 3 reported that sub-chronic PCP administration impairs reversal learning ability in an operant task, as demonstrated by reduced percent correct responding in the reversal phase of the reversal learning task. It was found that a D1 agonist (SKF-38398), a 5-HT1A partial agonist (buspirone), a 5-HT2C antagonist (SB-243213A) and an agonist and positive allosteric modulator of the alpha 7 nACh receptor (PNU-282987 and PheTQS respectively) are able to reverse the sub-chronic PCP-induced deficit in reversal learning. Although many antipsychotics have affinity for muscarinic M1 and histamine H1 receptors, selective agents at these receptors were not able to improve the PCP-induced deficit. In chapter 4, the atypical antipsychotics, clozapine and risperidone, when given alone to naïve rats had no effect on reversal learning. Haloperidol when given to naïve rats impaired performance at the highest dose. Sub-chronic PCP was again found to impair reversal learning performance. Investigative experiments revealed that the 2 min time-out could be important as a cue. Following a double reversal, olanzapine-treated rats lost the ability to switch between the rules, whereas clozapine and risperidone-treated rats could perform the double reversal. Experiments with the extended (15 min) reversal phase could allow the investigation of the time-course effects of antipsychotics or selective compounds. The studies presented in chapter 5 found a reduction in gamma oscillations in the CA3 region of the hippocampus, following sub-chronic PCP treatment (2-5 weeks post treatment) that was paralleled by a deficit in parvalbumin immunoreactive (IR) cell density, at a similar time point (2 weeks post treatment). In contrast, a time-dependent increase in gamma oscillations was observed (6-8 weeks post treatment), at which point parvalbumin IR cell density was unchanged (8 weeks post treatment). Gamma oscillations were unchanged in the prefrontal cortex (PFC) following the PCP treatment regime. Locomotor activity tests were also carried out to ensure that the sub-chronic PCP treatment was successful. In-vivo microdialysis revealed that vehicle-treated rats show an increase in dopamine in the PFC which is selective for the retention trial of the novel object recognition task. PCP-treated rats were unable to distinguish between the novel and familiar objects and the increase in dopamine observed in vehicle rats was absent. As a control experiment it was also shown that sub-chronic PCP did not induce anxiety-like symptoms in the elevated plus maze and open field tests. These studies suggest that sub-chronic PCP induces cognitive deficits in behavioural tasks, and these deficits may be due to GABAergic mediated processes in the hippocampus and dopaminergic dysfunction in the PFC. These behavioural and neurochemical results are concurrent to findings observed in schizophrenia.

Yes / Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D1-like receptor agonist, SKF-38393, to improve PCPinduced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (Pb0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D1-like receptor antagonist (Pb0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (Pb0.001); SKF-38393 (6.0 mg/kg) improved this PCPinduced deficit, an effect antagonised by SCH-23390 (Pb0.05). These results suggest a role for D1-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

Yes / It has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia.