The orexin/hypocretin system is important for reward-seeking behaviors, however less is known about its function in non-homeostatic feeding. Environmental influences, particularly cues for food can stimulate feeding in the absence of hunger and lead to maladaptive overeating behavior. The key components of the neural network that mediates this cue-induced overeating in sated rats include lateral hypothalamus, amygdala, and medial prefrontal cortex (mPFC), yet the neuropharmacological mechanisms within this network remain unknown. The current study investigated a causal role for orexin in cue-driven feeding, and examined the neural substrates through which orexin mediates this effect. Systemic administration of the orexin-1 receptor (OX1R) antagonist SB-334867 had no effect on baseline eating, but significantly reduced cue-driven consumption in sated rats. Complementary neural analysis revealed that decreased cue-induced feeding under SB-334867 increased Fos expression in mPFC and paraventricular thalamus. These results demonstrate that OX1R signaling critically regulates cue-induced feeding, and suggest orexin is acting through prefrontal cortical and thalamic sites to drive eating in the absence of hunger. These findings inform our understanding of how food-associated cues override signals from the body to promote overeating, and indicate OX1R antagonism as a potential pharmacologic target for treatment of disordered eating in humans.

The peripartum period is associated with the onset of behaviors that shelter, feed and protect young offspring from harm. The neural pathway that regulates caregiving behaviors has been mapped in female rats and is conserved in mice. However, rats rely on late gestational hormones to shift their perception of infant cues from aversive to attractive, whereas laboratory mice are "spontaneously" maternal, but their level of responding depends on experience. For example, pup-naïve virgin female mice readily care for pups in the home cage, but avoid pups in a novel environment. In contrast, pup-experienced virgin mice care for pups in both contexts. Thus, virgin mice rely on experience to shift their perception of infant cues from aversive to attractive in a novel context. We hypothesize that alterations in immediate early gene activation may underlie the experience-driven shift in which neural pathways (fear/avoidance versus maternal/approach) are activated by pups to modulate context-dependent changes in maternal responding. Here we report that the effects of sodium butyrate, a drug that allows for an amplification of experience-induced histone acetylation and gene expression in virgins, are comparable to the natural onset of caregiving behaviors in postpartum mice and induce postpartum-like patterns of immediate early gene expression across brain regions. These data suggest that pups can activate a fear/defensive circuit in mice and experience-driven improvements in caregiving behavior could be regulated in part through decreased activation of this pathway.

Maternal behavior is a defining characteristic of mammals, which is regulated by a core, conserved neural circuit. However, mothering behavior is not always a default response to infant conspecifics. For example, initial fearful, fragmented or aggressive responses toward infants in laboratory rats and mice can give way to highly motivated and organized caregiving behaviors following appropriate hormone exposure or repeated experience with infants. Therefore hormonal and/or experiential factors must be involved in determining the extent to which infants access central approach and avoidance neural systems. In this review we describe evidence supporting the idea that infant conspecifics are capable of activating distinct neural pathways to elicit avoidant, aggressive and parental responses from adult rodents. Additionally, we discuss the hypothesis that alterations in transcriptional regulation within the medial preoptic area of the hypothalamus may be a key mechanism of neural plasticity involved in programming the differential sensitivity of these neural pathways.

The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup‐induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non‐aggressive male mice and alters the pattern of pup‐induced IEG expression across a fear/defensive neural circuit.

Whereas the majority of mammalian species are uni-parental with the mother solely provisioning care for young conspecifics, fathering behaviors can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice.Further, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes, however the extent to which infants are capable of accessing this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus than in an approach/attraction circuit involving the ventral tegmental area.However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of neuronal activation and behavior. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. Here, we asked whether HDACi treatment would impact behavioral response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. Our results indicate that systemic HDACi treatment induces spontaneous caregiving behavior in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit.