Biology subjects

Galea, L. A.

Publications and source records attributed to Galea, L. A..

5 recordsLinked to original sources

bioRxiv2025

Conjugated GLP-1 and Estradiol Treatment as a Novel Treatment for Age-related Cognitive Decline in Males and Females

Middle age represents a critical window for metabolic and cognitive health, particularly in the context of rising obesity and diabetes rates. Glucagon-like peptide-1 (GLP-1)-based therapies, which regulate blood glucose and body weight, show sex-specific effects, with estradiol potentiating their metabolic benefits. However, research on GLP-1s cognitive and neuroprotective roles has largely been conducted in males. Here, we investigated the effects of GLP-1 conjugated to estradiol (GE2) on metabolism, cognition, cytokine levels and neurogenesis in the dentate gyrus of middle-aged male and female rats fed a standard (SD) or Western (WD) diet. In both sexes, WD increased body weight and plasma leptin levels, regardless of sex. GE2 treatment led to weight loss, enhanced cued and contextual fear memory, reduced cytokine levels in the hippocampus in SD rats, and increased neurogenesis in the dorsal dentate gyrus (DG), regardless of sex. Sex-specific differences were observed in fat distribution, glucose regulation, central cytokine levels, and neuroplasticity after WD and GE2 treatment. In females only, GE2 reduced visceral (gonadal) fat, reduced cytokines in the dorsal hippocampus, and improved basal blood glucose in response to a WD. In males only, GE2 restored neurogenesis in the DG after WD exposure, and reduced cytokine levels in the amygdala. These findings suggest that although WD increased body weight and GE2 improved associative learning in both sexes, both WD and GE2 had differential affects on metabolic hormones, insulin regulation, cytokine levels and neuroplasticity. Our findings underscore the importance of sex-specific approaches in metabolic and neuroprotective therapeutics in middle age.

neuroscience↗

bioRxiv2021

Sex and estradiol differences in MAPK and Akt cell signaling across subregions of the hippocampus

IntroductionRapid effects of estrogens within the hippocampus of rodents are dependent upon cell signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens and across the anatomical longitudinal axis has been overlooked. MethodsGonadally-intact female and male rats were given either vehicle or physiological systemic low (1.1{micro}g/kg) or high (37.3{micro}g/kg) doses of 17{beta}-estradiol thirty minutes prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17{beta}-estradiol. Brains were extracted and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key MAPK and Akt cascade phosphoproteins. ResultsIntact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3{beta}, pp70S6K) than males in the DG (dorsal, ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17{beta}-estradiol on cell signalling occurred in OVX animals. In OVX animals, 17{beta}-estradiol increased cell signalling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, pGSK-3{beta}) in the CA1 and pERK1/2 and pJNK DG. Discussion/ConclusionsSystemic 17{beta}-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus dependent on reproductive status and intact females have greater expression of Akt phosphoproteins than intact males across the hippocampus. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.

neuroscience↗

bioRxiv2019

Sex differences in cortisol and memory following acute social stress in amnestic mild cognitive impairment

ObjectiveOlder adults with amnestic mild cognitive impairment (aMCI) develop Alzheimers type dementia approximately ten times faster annually than the normal population. Adrenal hormones are associated with aging and cognition. We investigated the relationship between acute stress, cortisol, and memory function in aMCI with an exploratory analysis of sex. MethodSalivary cortisol was sampled diurnally and during two test sessions, one session with the Trier Social Stress Test (TSST), to explore differences in the relationship between cortisol and memory function in age-normal cognition (NA) and aMCI. Participants with aMCI (n=6 women, 9 men; mean age=75) or similarly aged NA (n=9 women, 7 men, mean age=75) were given tests of episodic, associative, and spatial working memory with a psychosocial stressor (TSST) in the second session. ResultsThe aMCI group performed worse on the memory tests than NA as expected, and males with aMCI had elevated cortisol levels on test days. Immediate episodic memory was enhanced by social stress in NA but not in the aMCI group, indicating that stress-induced alterations in memory are different in individuals with aMCI. High cortisol was associated with impaired performance on episodic memory in aMCI males only. Cortisol in Session 1 moderated the relationship with spatial working memory, whereby higher cortisol was associated with worse performance in NA, but better spatial working memory in aMCI. In addition, effects of aMCI on perceived anxiety in response to stress exposure were moderated by stress-induced cortisol in a sex-specific manner. ConclusionsWe show effects of aMCI on Test Session cortisol levels and effects on perceived anxiety, and stress-induced impairments in memory in males with aMCI in our exploratory sample. Future studies should explore sex as a biological variable as our findings suggests that effects at the confluence of aMCI and stress can be obfuscated without sex as a consideration.

neuroscience↗

bioRxiv2019

Selective activation of estrogen receptors α and β: Implications for depressive-like phenotypes in female mice exposed to chronic unpredictable stress

The estrogen receptor (ER) mechanisms by which 17{beta}-estradiol influences depressive-like behaviour have primarily been investigated acutely and not within an animal model of depression. Therefore, the current study aimed to dissect the contribution of ER and ER{beta} to the effects of 17{beta}-estradiol under non-stress and chronic stress conditions. Ovariectomized (OVX) or sham-operated mice were treated chronically (47 days) with 17{beta}-estradiol (E2), the ER{beta} agonist diarylpropionitrile (DPN), the ER agonist propylpyrazole-triol (PPT), or vehicle. On day 15 of treatment, mice from each group were assigned to Chronic Unpredictable Stress (CUS; 28 days) or non-CUS conditions. Mice were assessed for anxiety- and depressive-like behaviour and hypothalamic-pituitary-adrenal (HPA) axis function. Cytokine and chemokine levels, and postsynaptic density protein 95 were measured in the hippocampus and frontal cortex, and adult hippocampal neurogenesis was assessed. Overall, the effects of CUS were more robust that those of estrogenic treatments, as seen by increased immobility in the tail suspension test (TST), reduced PSD-95 expression, reduced neurogenesis in the ventral hippocampus, and HPA axis negative feedback dysregulation. However, we also observe CUS-dependent and -independent effects of ovarian status and estrogenic treatments. The effects of CUS on PSD-95 expression, the cytokine milieu, and in TST were largely driven by PPT and DPN, indicating that these treatments were not protective. Independent of CUS, estradiol increased neurogenesis in the dorsal hippocampus, blunted the corticosterone response to an acute stressor, but increased anxiety-like behaviour. These findings provide insights into the complexities of estrogen signaling in modulating depressive-like phenotypes under non-stress and chronic stress conditions.

neuroscience↗

bioRxiv2019

Androgens enhance adult hippocampal neurogenesis in males but not females in an age-dependent manner

Androgens (testosterone and dihydrotestosterone) increase adult hippocampal neurogenesis by increasing new neuron survival in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in females and whether the effect is age-dependent. We investigated the effects of dihydrotestosterone, a potent androgen, on neurogenesis in adult and middle-aged males and females. Rats were gonadectomized and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU). The following day rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and new neuron survival (BrdU and BrdU/NeuN) in the hippocampus of male and female rats using immunohistochemistry. As expected, DHT increased new neuron survival in young males but surprisingly not in middle-aged male rats. In females, DHT did not significantly affect adult neurogenesis in young or middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

neuroscience↗