Biology subjects

Guler, A. D.

Publications and source records attributed to Guler, A. D..

7 recordsLinked to original sources

bioRxiv2026

LiFE, a multimodal circadian intervention, improves sleep, glycemic control, and recognition memory

In mammals, sleep is regulated by the central circadian system, which responds to environmental timing cues including light, exercise and availability of food. In this study, we developed a light-, food-, and exercise-based daily lifestyle intervention (LiFE) that combines the effects of multiple circadian entrainment cues on central clock function, ultimately strengthening central clock rhythms. In wild-type (WT) mice, LiFE consolidated nocturnal activity, enhanced suprachiasmatic nucleus rhythmicity, and increased sleep time. Despite comparable caloric intake to control conditions, LiFE lowered baseline blood glucose, reduced glycemic variability, and improved glucose tolerance. We found long-term LiFE treatment improved recognition memory in WT mice. Sleep and circadian disruption are commonly observed in patients with Alzheimers disease (AD), the most prevalent neurodegenerative disorder. We applied long-term LiFE treatment in two AD mouse models (5xFAD and 5xFAD/PS19). Alongside a subtle reduction in AD histopathology, LiFE produced near-significant trends toward improved motor performance and recognition memory. Together, these findings support multimodal circadian chronotherapy as a non-pharmacological approach in which integrated light, feeding, and exercise entrainment promotes sleep and metabolic health.

neuroscience↗

bioRxiv2024

A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs

Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections and complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here, we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behavior. This approach revealed that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtail hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings reveal a dedicated neural circuit through which small molecule GLP1RAs modulate reward processing, suggesting broad therapeutic potential in conditions of dysregulated dopamine signaling including substance use disorder and binge eating.

neuroscience↗

bioRxiv2023

Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis.

neuroscience↗

bioRxiv2023

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

neuroscience↗

bioRxiv2023

Altered circadian behavior and light sensing in mouse models of Alzheimer's disease

Circadian symptoms have long been observed in Alzheimers disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a six hour advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, an SCN-independent circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

neuroscience↗

bioRxiv2023

A leptin-responsive hypothalamic circuit inputs to the circadian feeding network

Salient cues, such as the rising sun or the availability of food, play a crucial role in entraining biological clocks, allowing for effective behavioral adaptation and ultimately, survival. While the light-dependent entrainment of the central circadian pacemaker (suprachiasmatic nucleus, SCN) is relatively well defined, the molecular and neural mechanisms underlying entrainment associated with food availability remains elusive. Using single nucleus RNA sequencing during scheduled feeding (SF), we identified a leptin receptor (LepR) expressing neuron population in the dorsomedial hypothalamus (DMH) that upregulates circadian entrainment genes and exhibits rhythmic calcium activity prior to an anticipated meal. We found that disrupting DMHLepR neuron activity had a profound impact on both molecular and behavioral food entrainment. Specifically, silencing DMHLepR neurons, mis-timed exogenous leptin administration, or mis-timed chemogenetic stimulation of these neurons all interfered with the development of food entrainment. In a state of energy abundance, repetitive activation of DMHLepR neurons led to the partitioning of a secondary bout of circadian locomotor activity that was in phase with the stimulation and dependent on an intact SCN. Lastly, we discovered that a subpopulation of DMHLepR neurons project to the SCN with the capacity to influence the phase of the circadian clock. This leptin regulated circuit serves as a point of integration between the metabolic and circadian systems, facilitating the anticipation of meal times.

neuroscience↗

bioRxiv2020

Effect of the p75 Neurotrophin Receptor on Glycemic Control of Obese Mice during Time-Restricted Feeding

Circulating glucose regulates organismal energy homeostasis and is tightly controlled in response to feeding behavior. In overweight individuals, glucose homeostasis is often perturbed due to resistance to normal satiety signals, such as insulin and leptin, leading to type 2 diabetes and its attendant complications. An emerging dietary intervention, time-restricted feeding (TRF), aims to ameliorate the adverse metabolic consequences of obesity, however, its effectiveness on glucose control is uncertain. Here, we demonstrate that TRF is only transiently effective in reducing pre-meal serum glucose levels in obese mice lacking leptin. However, in Ob/Ob mice that also lack a gene known to suppress behavior associated with TRF, the p75 neurotrophin receptor (p75NTR), a sustained reduction of glucose levels is observed. These results suggest that the effectiveness of TRF on glycemic control can be enhanced with concurrent targeting of modulators of glucose homeostasis and TRF response.

physiology↗