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1. Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice

   https://doi.org/10.1038/s41386-022-01326-0  

   Kesner, Andrew J.; Mateo, Yolanda; Abrahao, Karina P.; Ramos-Maciel, Stephanie; Pava, Matthew J.; Gracias, Alexa L.; Paulsen, Riley T.; Carlson, Hartley B.; Lovinger, David M. (July 2022, Neuropsychopharmacology)

   Abstract Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them. 

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2. Early-life vocalizations and adult auditory brainstem responses in California mice (Peromyscus californicus)

   https://doi.org/10.1016/j.physbeh.2025.115011  

   Arquilla, April M; Kokash, Jamiela; Rumschlag, Jeffrey A; Wilson, Kerianne M; Razak, Khaleel A; Saltzman, Wendy (October 2025, Physiology & Behavior)

   Mammalian infants rely on vocalizations to elicit care from their parents. In adult females, behavioral and neural responses to infant cries may change during the onset of motherhood; however, parenthood-associated plasticity in auditory processing is not well understood, especially in fathers. We characterized pup vocalizations from postnatal day (PND) 1 to PND 21 in biparental California mice (Peromyscus californicus) and assessed auditory brainstem responses to pure tones in adult virgins and parents of both sexes to test the hypothesis that auditory processing changes with the onset of parenthood, particularly in response to pup-relevant sound frequencies. Pups’ call rate dropped sharply after PND 13, and pups from smaller litters vocalized more than pups from larger litters. Syllable duration was significantly shorter at PND 16–21 than all other ages. Overall, the minimum frequency of vocalizations and minimum, fundamental, and harmonic frequency power increased with age. Minimum frequency was highest after PND 10, and power for all frequencies peaked at PND 13–15. Hearing thresholds for 24 kHz stimuli were lower in parents than in virgins regardless of sex, and thresholds for 4 kHz were lower in females than in males. Auditory nerve response latencies were shorter in parents than in virgins at 4 kHz and shorter in females than in males at 8 kHz. In sum, our findings provide a spectral breakdown of earlylife vocalizations and provide evidence that auditory processing can be influenced by reproductive status in both males and females in a biparental species. 

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3. Age and Sex as Determinants of Acute Domoic Acid Toxicity in a Mouse Model

   https://doi.org/10.3390/toxins15040259  

   Hendrix, Alicia M.; Lefebvre, Kathi A.; Bowers, Emily K.; Stuppard, Rudolph; Burbacher, Thomas; Marcinek, David J. (April 2023, Toxins)

   The excitatory neurotoxin domoic acid (DA) consistently contaminates food webs in coastal regions around the world. Acute exposure to the toxin causes Amnesic Shellfish Poisoning, a potentially lethal syndrome of gastrointestinal- and seizure-related outcomes. Both advanced age and male sex have been suggested to contribute to interindividual DA susceptibility. To test this, we administered DA doses between 0.5 and 2.5 mg/kg body weight to female and male C57Bl/6 mice at adult (7–9-month-old) and aged (25–28-month-old) life stages and observed seizure-related activity for 90 min, at which point we euthanized the mice and collected serum, cortical, and kidney samples. We observed severe clonic–tonic convulsions in some aged individuals, but not in younger adults. We also saw an association between advanced age and the incidence of a moderately severe seizure-related outcome, hindlimb tremors, and between advanced age and overall symptom severity and persistence. Surprisingly, we additionally report that female mice, particularly aged female mice, demonstrated more severe neurotoxic symptoms following acute exposure to DA than males. Both age and sex patterns were reflected in tissue DA concentrations as well: aged mice and females had generally higher concentrations of DA in their tissues at 90 min post-exposure. This study contributes to the body of work that can inform intelligent, evidence-based public health protections for communities threatened by more frequent and extensive DA-producing algal blooms. 

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4. Prepubertal gonadectomy reveals sex differences in approach-avoidance behavior in adult mice

   https://doi.org/10.1016/j.yhbeh.2019.104641  

   Delevich, Kristen; Hall, Chris D.; Piekarski, David; Zhang, Yuting; Wilbrecht, Linda (February 2020, Hormones and behavior)

   null (Ed.)

   Adolescence is a developmental period that is associated with physical, cognitive, and affective maturation and a time when sex biases in multiple psychiatric diseases emerge. While puberty onset marks the initiation of adolescence, it is unclear whether the pubertal rise in gonadal hormones generates sex differences in approach-avoidance behaviors that may impact psychiatric vulnerability. To examine the influence of pubertal development on adult behavior, we removed the gonads or performed sham surgery in male and female mice just prior to puberty onset and assessed performance in an odor-guided foraging task and anxiety-related behaviors in adulthood. We observed no significant sex differences in foraging or anxiety-related behaviors between intact adult male and female mice but found significant differences between adult male and female mice that had been gonadectomized (GDX) prior to puberty onset. GDX males failed to acquire the odor-guided foraging task, showed reduced locomotion, and exhibited increased anxiety-like behavior, while GDX females showed the opposite pattern of behavior. These data suggest that puberty may minimize rather than drive differences in approach-avoidance phenotypes in male and female mice. 

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5. D-methionine improves spatial navigation and attenuates oxidative stress and amyloid pathology in a sex-specific manner

   https://doi.org/10.1177/13872877261444307  

   Peck, Mackenzie R; Chapman, Jenelle E; Hill, Tiarra; Quinn, Kathleen; Ikiz, Erol D; Lopez, Angel; Hascup, Erin R; Bae, Chilman; Hascup, Kevin N (June 2026, Journal of Alzheimer’s Disease)

   BackgroundOxidative stress and maladaptive neuroimmune activation contribute to cognitive decline in Alzheimer's disease (AD) and represent therapeutic targets beyond amyloid-centered approaches. ObjectiveTo determine whether oral D-methionine (D-Met), a redox-active amino acid, reduces amyloid pathology and lipid peroxidation and confers disease-modifying benefits in AD models. MethodsMale and female APP/PS1 and APP^NL−Fmice with advanced AD pathology received oral D-Met or vehicle. Behavioral assessments included locomotor activity and hippocampal-dependent spatial learning and memory. Amyloid burden, lipid peroxidation, peripheral metabolic, and inflammatory markers, and hippocampal microglial phenotypes were evaluated. ResultsD-Met did not alter locomotor or exploratory behavior but improved spatial memory recall in both sexes of APP/PS1 mice and in female APP^NL−Fmice. APP^NL−Fmales exhibited improved Morris water maze learning. Amyloid pathology was region-specifically reduced, including decreased hippocampal plaque size in male APP^NL−Fmice, reduced cortical plaque size in female APP/PS1 mice, and lower soluble amyloid-β (Aβ)₄₂in male APP/PS1 mice. Lipid peroxidation was reduced only in female APP^NL−Fmice. D-Met induced pronounced sex-dependent peripheral effects, increasing adiposity and pro-inflammatory adipose signaling in males, while reducing perigonadal white adipose tissue IL-6 expression in female APP^NL−Fmice. In the hippocampus, D-Met decreased microglial activation, with female APP^NL−Fmice showing reduced Iba1 and disease-associated microglial markers and increased Axl expression. ConclusionsShort-term D-Met acts as a metabolic and redox modulator with amyloid-lowering effects mediated by improved microglial function. Therapeutic efficacy is strongly sex- and model-dependent, with the greatest benefit observed in female APP^NL−Fmice. 

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