Previous research has demonstrated body weight gain in rats after lesions to the posterodorsal amygdala. Likewise, a recent study also found increased body weight as a result of knife-cuts of the stria terminalis, just as it exits the amygdala. In the present study, these findings were extended and previous studies replicated by producing 1) lesions in the stria terminalis as it travels dorsally through the brain, 2) coronal knife-cuts anterior to the ventromedial hypothalamus, and 3) axon-sparing lesions of the posterodorsal amygdala using ibotenic acid. Both lesions of the dorsal stria terminalis and coronal knife-cuts anterior to the ventromedial hypothalamus resulted in significant weight gain in female rats as compared to controls. The failure of previous research to find effects after these treatments is attributed to the use of male animals. In addition, examination of anterograde degeneration using an amino-cupric-silver stain in two rats with knife-cuts revealed degenerating terminals in the shell of the VMH and the premammillary nuclei, indicating that the dorsal component of the stria terminalis had been severed. The results of ibotenic acid lesions of the posterodorsal amygdala are unable to be reported due to the inability to histologically verify the lesions. This may have been cause by acid seepage into the lateral ventricles. While the amygdala can not be confirmed as the origin of information concerning body weight regulation and food intake, the stria terminalis does seem to carry this information, exerting an inhibitory influence on the ventromedial hypothalamus.

Electrolytic lesions of the ventromedial hypothalamus produce an obesity syndrome in experimental animals characterized by behavioural and metabolic disturbances. Historically, theories of VMH obesity have considered a single disturbance, either behavioural or metabolic, to be the primary effect of the lesion, which in turn causes other components of the syndrome. An alternative view suggests that VMH lesions simultaneously disturb both behavioural and metabolic mechanisms due to the anatomical proximity of these mechanisms in the hypothalamus. Therefore, more discrete lesions in the VMH may produce some syndrome components but not others. This thesis presents a series of experiments that test this "dissociative" perspective of the VMH obesity syndrome. First, rats having different hypothalamic ablations were compared on: caloric intakes on a series of test diets, body weight changes, and body fat. Bilateral parafornical hypothalamic knife cuts (PFKC) that spared the ventromedial hypothalamic nucleus (VMN), produced overeating and weight gain characteristic of VMH lesions. However, measurement of percentage body fat (i.e. level of obesity) indicated that PFKC rats were less obese than VMH rats, even though PFKC lesions produced a greater hyperphagia and weight gain than VMH lesions. In contrast, lesions restricted to VMN produced obesity, but did not produce hyperphagia or weight gain. Since parafornical knife cuts produced a greater hyperphagia than VMH lesions, it is possible that VMN damage actually reduces caloric intake in VMH rats. To test this hypothesis, the effects of VMH, PFKC, and combined PFKC/VMN lesions on caloric intake and body weight were compared. PFKC and VMH lesions produced hyperphagia and weight gain. However, knife cuts were not significantly more effective than VMH lesions for producing these disturbances in this experiment. Therefore, PFKC lesions do not invariably produce a greater hyperphagia than VMH lesions. Furthermore, VMN lesions had no effect on the level of overeating or weight gain in rats bearing PFKC lesions. Therefore, damage to VMN does not reduce the hyperphagia produced by PFKC lesions. Finally, the effects of these different hypothalamic manipulations on metabolic measures were determined. To eliminate the confound of hyperphagia on metabolic variables, all lesion rats were fed a daily food ration sufficient to maintain their body weight at the level of controls. VMH and PFKC lesions resulted in elevated parasympathetic tone, indicated by elevated basal gastric acid secretion. VMN lesions did not affect gastric acid secretion. In contrast, only VMH and VMN lesions produced obesity when overeating was prevented. PFKC rats did not become obese. These experiments demonstrate that separate hypothalamic mechanisms underly the hyperphagia and obesity characteristic of VMH lesions. Furthermore, different mechanisms underly obesity and elevated parasympathetic tone following VMH lesions. Therefore, these observations support a dissociative model of the VMH obesity syndrome. / Thesis / Doctor of Philosophy (PhD)

Serotonin has been implicated as a modulator of feeding behavior. This experiment was designed to alter brain serotonin levels through dietary means in hypothalamic ventromedial-lesioned and unlesioned rats. Daily food, water, and animal weights were measured. The purpose was to determine if VMH lesions altered the feeding pattern found in unlesioned rats. Although food intake for tryptophanenriched diets and tryptophan-deficient diets did not differ from their respective control groups, in some cases gross animal weights did differ significantly between experimental and control groups and between lesioned and unlesioned groups. A proposed model explains how a "low" energy signal and a "high" protein signal cycles amino acids through gluconeogenesis to comPensate for an energy deficit.

Our senses are constantly bombarded with information. How does the brain integrate such a variety of inputs to generate appropriate behaviours? Innate defensive behaviours are a good model to address this question. They are essential for animal survival and the brain circuits that control them are highly conserved across species. Moreover, the sensory inputs and behavioural outputs can be well defined and reliably reproduced in the lab. This allows us to study function of the individual components of the circuit controlling these behaviours. Ventromedial hypothalamus (VMH) is a key brain region for controlling responses to predators; it has been shown that inactivating the VMH can reduce defensive behaviours. Interestingly, activating the VMH output neurons (SF1+ cells) can produce a variety of different behaviours, from immobility to escape, depending on the intensity of activation. During my PhD I used a variety of approaches to address the question of the function of the VMH in control of defensive behaviours. At first I hypothesised that the VMH might act as a centre responsible for choosing an appropriate behavioural response according to the stimulus. I set to investigate how different activation levels of SF1+ neurons can produce such different behavioural outputs, and how this activity is modulated in vivo in response to predator stimuli. I began the project by quantifying mouse defensive behaviours in response to olfactory and auditory predator cues, as well as to the optogenetic activation of SF1+ neurons. I then questioned whether there was heterogeneity within the population of SF1+ neurons, which could explain their ability to trigger different behaviours. I performed patch clamp recordings from acute brain slices and conducted a study of the electrophysiological properties of SF1+ neurons. I next investigated how SF1+ neurons integrate excitatory inputs from the medial amygdala, a region which receives olfactory inputs from the accessory olfactory bulb. By combining optogenetics with slice electrophysiology and behavioural assessment, I described the physiology and relevance of this connection. Finally, I investigated in vivo activity in the VMH in response to predator cues by performing calcium imaging of the VMH neurons in freely moving mice. By presenting different sensory stimuli, I addressed the question of heterogeneity of the input pattern to the VMH neurons and the relationship between the VMH activity and the behavioural output. Taken all together, the results of this project have led to a hypothesis whereby the function of the VMH is to facilitate rather than directly control the choice of an appropriate behavioural response.

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