Editorial: Sex as a biological variable in the neurocircuitry of motivated behavior

Paul Leon Brown^1*Polymnia Georgiou²Amy Stave Kohtz³Antoniette Michelle Maldonado-Devincci⁴

• ¹University of Maryland Baltimore School of Medicine, Baltimore, United States
• ²University of Wisconsin-Milwaukee, Milwaukee, United States
• ³The University of Mississippi Medical Center, Jackson, United States
• ⁴North Carolina Agricultural and Technical State University, Greensboro, United States

primarily include midbrain dopaminergic nuclei and their projections to the ventral striatum, but also includes upstream hypothalamic and amygdalar inputs, downstream basal ganglia targets, and several other sensory, limbic, sub-cortical, and cortical regions.Signaling through these pathways allows an organism to integrate salient sensory input and translate that into actions that fulfill a biological need (Stuber, 2023).Motivational and reward-processing disruptions are core features across psychiatric and neurological diseases, including major depressive disorder, schizophrenia, substance-use disorder, and Parkinson's disease. For this reason, translational researchers have modeled several aspects of reward processing in animals to better understand the neurocircuitry that regulates motivated behavior, under both normal and pathological conditions. The use of such models to develop better treatment and therapeutics for psychiatric and neurological patients that present with impaired motivation is a continuing goal of behavioral neuroscience (Der-Avakian et al, 2016).In addition, many of the conditions listed above have prevalence, symptomatology, and prognoses that can vary based on the sex of the individual. Diagnoses of unipolar depression are higher in women, but substance-use disorder is more prevalent in men.While schizophrenia is equally common by sex, males are more likely to have onset in the late juvenile/early adulthood period and with more severe cognitive symptoms than women. And pharmacological treatment for many psychiatric conditions varies by sex due to differences in physiological makeup (i.e. drug metabolism and clearance) or interactions with circulating gonadal hormones. Consequently, it is important to consider sex as a biological variable in the study as it relates to these 42 disorders (Gobinath et al, 2017). 43 that incubation of craving for self-administered oxycodone is elevated in male rats and 64 that, while extended oxycodone administration dysregulates the estrous cycle, there is 65 reduced short-and long-term craving in estrus phase rats. 66 Alcohol-use disorder is epidemiologically significant, and a disorder that has shown 67 sex differences in prevalence and pattern of development. Faccidomo et al (2025) confirm 68 that, in mice, escalation of ethanol consumption is greater in females than males after an 69 initial self-administration period. Antagonism of AMPA receptors, implicated in alcohol 70 use disorder, reduces response rates equivalently in both sexes. Shobande et al ( 2026) 71 used an adolescent intermittent ethanol (AIE) vapor model and found modest, sex-and 72 withdrawal-dependent effects on affective behavior, with metabolomic shifts across 73 serum, fecal, and liver samples most pronounced in males shortly after exposure and 74 diminished with longer withdrawal. 75 Cocaine is another abused substance showing use patterns that can be modulated 76 by estrogen in female rodents, but it is unknown whether estrogens have a similar effect 77 in males. Alvarado-Toress et al (2024) investigate the role of estrogen on cocaine seeking 78 in male rats using an aromatase inhibitor. They find that a low dose of fadrozole facilitates following cocaine self-administration. 81 Hippocampal function is important to memory retrieval and alter cue-induced 82 substance use. Berry et al (2024) antagonism of dorsal hippocampal beta-83 adrenergic receptors alters cocaine conditioned place preference in a sex manner. While all receptors drive conditioned place preference in male rats, in female 85 rats beta1 receptors drive retrieval and beta2 receptors drive acquisition and retention. 86 Like reinforcing stimuli, aversive stimuli also influence motivated behavior. Bell et 87 al (2023) demonstrate that the lateral habenula, an aversion activated brain nucleus, has 88 differing inhibitory strength over dopamine firing by sex in rats. Transient inhibition 89 commonly seen with habenular activation is of greater duration in male rats and more 90 likely to be followed by rebound excitation. 91 Finally, Kniffin and Briand (2024) review several regions of the brain and the role 92 that sex differences in glutamatergic transmission may play in reward. These include 93 differences in synaptic structure, strength, and plasticity. These differences are not 94 uniform across regions discussed, leading to convergent and divergent mechanisms of 95 glutamate transmission by sex. Animal research, such as these studies listed above, will continue to inform how 98 sex differences are incorporated into novel therapeutic treatments for pathological 99 conditions. However, there are caveats to consider. To what degree are sex differences 100 more influential than individual variability? Are sex differences found in animal (or human) 101 research of sufficient size to be of clinical and epidemiological relevance? How well do 102 the animal models translate to the human condition? There is no doubt that expanding 103 scientific knowledge is laudable, but that knowledge is more impactful if it can lead to 104 targeted treatment that helps improve the overall health of the population. By increasing 105 focus on the influence of sex on motivated behavior, it is our hope that such improvements 106 can be achieved. 107 108 or financial relationships that could be construed as a potential conflict of interest. 120 121