Food intake requires a complex interplay of signals from central and peripheral systems as well as external stimuli, which are integrated across multiple timescales to coordinate feeding behavior. Individuals make numerous decisions about food each day, including what to eat, how much to eat, and when. Traditionally, research examining the timing of food intake has done so on a 24-hour scale, examining the influence of appetite-stimulating and satiety signals on circadian rhythms of feeding behavior. However, individuals can keep track of time on multiple scales including in the milliseconds to minutes range, a form of timing known as interval timing. This perception of brief intervals supports associative learning and the formation of predictive relationships (C. V. Buhusi & Meck, 2005). Thus, interval timing is critical for learning and decision-making. However, despite the role of interval timing in decision-making and the frequency of food-related decisions, few studies have examined the relationship between appetitive signals and interval timing. Appetitive signals, including the neuropeptide Melanin concentrating hormone (MCH), are predominantly produced in the lateral hypothalamic area (LHA), a heterogenous brain region characterized by its role in energy homeostasis. I previously provided the first evidence that LHA neurons that produce MCH (LHA-MCH neurons) influence time-dependent food-seeking in a manner that depends on LHA subregion, sex, and estrous cycle stage. In particular, excitation of anterior LHA-MCH neurons selectively prolonged motivated food-seeking in females tested during diestrus, the period of the rodent estrous cycle when levels of circulating gonadal hormones are typically lower. This suggested a role for the nucleus accumbens (NAc), a ventral striatal region critically involved in reward processing, and circulating gonadal hormones like estradiol. This dissertation extends these findings by examining the role of LHA-MCH neurons that project to the nucleus accumbens (LHA-MCH to NAc) on time-dependent food-seeking. Specifically, I separately examined the effects of chemogenetic excitation of NAc-projecting neurons from posterior (LHAp; Chapter 2) and anterior (LHAa; Chapter 3) subregions of the LHA in intact female rats. While chemogenetic excitation of LHAp-MCH to NAc neurons failed to produce behavioral effects on time-dependent food-seeking, excitation of LHAa-MCH to NAc neurons influenced responding selectively during diestrus. Interestingly, however, these effects were in the opposite direction than expected: chemogenetic excitation of LHAa-MCH to NAc neurons reduced food-seeking after the omission of an expected food reward. Finally, I directly examined the influence of estrogen on LHAa-MCH to NAc neuronal excitation by ovariectomizing rats (OVX) and testing them with and without estradiol replacement. Contrary to expectations, chemogenetic excitation of LHAa-MCH to NAc reduced post-criterion food-seeking in OVX rats treated with estradiol, rather than without. In short, the removal of peripheral estrogen through ovariectomy does not recapitulate effects of LHAa-MCH to NAc excitation during diestrus. This data indicates that motivational effects of LHAa-MCH to NAc neurons are sensitive to circulating gonadal hormones, including estrogen. Furthermore, these data indicate a role for LHAa-MCH to NAc neurons in guiding decisions to persevere or attenuate effortful food-seeking after the omission of an expected food reward.
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