Browsing by Author "Lukkes, Jodi"

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    Analyzing the Effects of Gonadal Hormones on Alcohol Seeking and Drinking in Alcohol-Preferring P Rats
    (2024-11) Haines, Kari M.; Czachowski, Cristine; Grahame, Nicholas; Logrip, Marian; Lukkes, Jodi
    Female and male rodents have shown differences in alcohol-seeking and -drinking behaviors, with female rodents typically consuming more alcohol than male rodents. Differences in gonadal hormones may provide one explanation for these sex differences. The current study used selectively bred female and male alcohol-preferring (P) rats to assess sex differences and the possible impacts of circulating gonadal hormones on alcohol seeking and drinking in an operant appetitive/consummatory paradigm. P rats were trained in operant boxes first for water and then 20% alcohol. Rats then underwent ovariectomy (OVX), castration (CAST), or sham surgeries. After recovery from surgery, rats that underwent OVX or CAST surgery then started receiving daily subcutaneous (s.c.) injections of either estradiol benzoate (E2), testosterone (T), or vehicle (Veh) which began five days prior to additional operant testing and lasted throughout the study. Rats were given a response requirement (RR) Monday-Thursday where they had 20-minutes to meet the required lever presses which resulted in 20-minute access to alcohol. Testing occurred over three weeks which resulted in 12 days of alcohol-drinking behavior. On Fridays, rats were given a 20-minute extinction session where number of lever presses were recorded which resulted in three days of alcohol-seeking behavior. Overall, females drank more alcohol than males in both training and testing. This was seen in both Veh and Sham rats. There were no sex differences in alcohol-seeking behavior. There was no effect of E2 or T in either sex as there were no differences in alcohol intake or lever presses during extinction compared to Veh groups. There were also no sex or group differences in blood ethanol concentrations (BEC), but BEC did correlate with alcohol intake. This study is one of the first examining gonadal hormones in a selectively bred line of rat that prefers to drink alcohol and is unique in that it included both females and males in each of the treatment groups. The activational effects of gonadal hormones may have a limited impact on alcohol-related behaviors in P rats, but more research is needed to make definitive conclusions about their role.
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    BMAL1 Overexpression in Suprachiasmatic Nucleus Protects from Retinal Neurovascular Deficits in Diabetes
    (bioRxiv, 2025-02-06) Mahajan, Neha; Luo, Qianyi; Lukkes, Jodi; Abhyankar, Surabhi D.; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
    The suprachiasmatic nucleus (SCN) regulates circadian rhythms and influences physiological and behavioral processes. Disruptions in circadian rhythms (CRD) are observed in type 2 diabetes (T2D), and importantly, CRD acts as an independent risk factor for T2D and its associated complications. BMAL1, a circadian clock gene, is vital for sustaining an optimal circadian rhythm and physiological function. However, the therapeutic potential of BMAL1 overexpression in the SCN to rectify the neurovascular deficits of T2D has yet to be investigated. In this study, db/db mice, a well-established model of T2D exhibiting arrhythmic behavior and the complications of diabetes, were injected stereotaxically with AAV8-Bmal1 or a control virus in the SCN to evaluate the protective effects of correcting the central clock on neurovascular deficits. Given the complex neurovascular network and the eye's unique accessibility as a transparent system, ocular complications were selected as a model to examine the neuronal functional, behavioral, and vascular benefits of correcting the central clock. BMAL1 overexpression normalized the circadian rhythms, as demonstrated by improvements in the free-running period. The retinal neuronal function improved on electroretinogram, along with optomotor behavior and visual acuity enhancements. Retinal vascular deficits were also significantly reduced. Notably, our approach helped decrease fat content in genetically predisposed obese animals. Since the SCN is known to regulate hepatic glucose production via sympathetic mechanisms, glycemic control, and pyruvate tolerance tests were conducted. Systemically, we observed improved glucose homeostasis in BMAL1-overexpressing mice alongside a substantial reduction in hepatic gluconeogenesis. BMAL1 overexpression lowered plasma norepinephrine and liver TH levels, indicating a protective regulation of adrenergic signaling. Thus, this study underscores the therapeutic potential of targeting circadian clock genes like BMAL1 in the SCN to alleviate metabolic and neurovascular deficits associated with T2D. Our research offers a compelling framework for integrating circadian rhythms into managing diabetes and its complications.
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    Follow Your Heart: Heart Rate Variability Reveals Sex Differences in Autonomic Regulation During Anxiety-Like Behavior and During Alcohol Drinking in Rats
    (2024-02) Frasier, Raizel Michele; Yoder, Karmen; Hopf, Woody; McKinzie, David; Lukkes, Jodi; Conroy, Susan
    Mental health conditions remain a substantial and costly challenge to society. Of note, women have a higher prevalence of anxiety disorders than men, and alcohol misuse in women has risen sharply in recent years. However, critical mechanisms underlying these observed sex differences remain incompletely understood. Measures of cardiac function, including heart rate (HR) and HR variability (HRV), reflect dynamic balance between the two opposing branches of the autonomic nervous system: sympathetic (SNS, “fight or flight”) and parasympathetic (PNS, “rest and digest”). Furthermore, recent evidence strongly suggests these measures are potential biomarkers for pathological states, including mental health conditions. To better understand sex differences in autonomic mechanisms related to pathological anxiety and alcohol misuse, we utilized cardiac telemetry to measure HR and HRV. This allowed observation of real-time autonomic tone in awake, freely behaving Wistar rats of both sexes. At baseline, female rats had greater HR and lower SNS influence than males, which concords with human studies. In both anxiety-like behavior and alcohol drinking studies, we observed that females tend to utilize a higher PNS influence to overcome challenge, whereas males tend to utilize higher SNS. Furthermore, female (but not male) baseline HR and HRV are related to within-task behavior, suggesting that baseline state impacts drinking and anxiety-like behavior in a sex-specific way. Again, these data concord with human research suggesting a similar PNS bias in women and SNS bias in men when responding, especially under challenge. Taken together, these data have contributed new knowledge to sex differences in autonomic engagement, especially for anxiety states and alcohol drinking. Importantly, these findings are likely translationally relevant for the development of novel, and more personalized, therapies.