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Death of a loved one is recognized as one of life's greatest stresses, and 10%–20% of bereaved individuals will experience a complicated or prolonged grieving period that is characterized by intense yearning for the deceased. The monogamous prairie vole (Microtus ochrogaster) is a rodent species that forms pair bonds between breeding partners and has been used to study the neurobiology of social behaviors and isolation. Male prairie voles do not display distress after isolation from a familiar, same‐sex conspecific; however, separation from a bonded female partner increases emotional, stress‐related, and proximity‐seeking behaviors. Here, we tested the investigatory response of male voles to partner odor during a period of social loss. We found that males who lost their partner spent significantly more time investigating partner odor but not non‐partner social odor or food odor. Bachelor males and males in intact pairings did not respond uniquely to any odor. Furthermore, we examined dopamine (DA) receptor mRNA expression in the anterior insula cortex (aIC), nucleus accumbens (NAc), and anterior cingulate (ACC), regions with higher activation in grieving humans. While we found some effects of relationship type on DRD1 and DRD2 expression in some of these regions, loss of a high‐quality opposite‐sex relationship had a significant effect on DA receptor expression, with pair‐bonded/loss males having higher expression in the aIC and ACC compared with pair‐bonded/intact and nonbonded/loss males. Together, these data suggest that both relationship type and relationship quality affect reunion‐seeking behavior and motivational neurocircuits following social loss of a bonded partner. [ABSTRACT FROM AUTHOR]

A rod-shaped appendage called a primary cilium projects from the soma of most central neurons in the mammalian brain. The importance of cilia within the nervous system is highlighted by the fact that human syndromes linked to primary cilia dysfunction, collectively termed ciliopathies, are associated with numerous neuropathologies, including hyperphagia-induced obesity, neuropsychiatric disorders, and learning and memory deficits. Neuronal cilia are enriched with signaling molecules, including specific G-protein-coupled receptors (GPCRs) and their downstream effectors, suggesting that they act as sensory organelles that respond to neuromodulators in the extracellular space. We previously showed that GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet–Biedl syndrome (BBS). Based on this finding, we hypothesized that mislocalization of ciliary GPCRs may impact receptor signaling and contribute to the BBS phenotypes. Here, we show that disrupting localization of the ciliary GPCR dopamine receptor 1 (D1) in male and female mice, either by loss of a BBS protein or loss of the cilium itself, specifically in D1-expressing neurons, results in obesity. Interestingly, the weight gain is associated with reduced locomotor activity, rather than increased food intake. Moreover, the loss of a BBS protein or cilia on D1-expressing neurons leads to a reduction in D1-mediated signaling. Together, these results indicate that cilia impact D1 activity in the nervous system and underscore the importance of neuronal cilia for proper GPCR signaling. [ABSTRACT FROM AUTHOR]

Paternal environmental perturbations, including cocaine intake, can affect the development and behavior of the offspring through epigenetic inheritance. However, the mechanism by which cocaine alters the male germ cells epigenome is almost unexplored. Here, we report that cocaine-treated male mice showed alterations on specific histone post-translational modifications (PTMs) including increased silent chromatin marks H3K9me3 and H3K27me3 and decreased active enhancer and promoter marks H3K27ac and H3K4me3 in isolated germ cells. Also, cocaine increased H3K9ac and H4K16ac levels, involved in the replacement of histones by protamines that take place at round spermatid stage. Cocaine also altered histones H3/H4 epigenetic enzymes by increasing acetyltransferase KAT8/MOF, deacetylase SIRT1 and methyltransferase KMT1C/G9A, and decreasing deacetylases HDAC1/2 and demethylase KDM1A/LSD1 protein levels. Moreover, a pre-treatment with dopamine receptor 1 (DRD1) antagonist SCH23390 (SCH) blocked cocaine effects on H3K4me3, H3K27me3, and H4K16ac epigenetic marks. Interestingly, treatment with SCH-only was able to modify most of the histone marks tested here, pointing to a dopamine role in controlling histone PTMs in germ cells. Taken together, our data suggest a key role for DRD1 in mediating cocaine-triggered epigenetic modifications related to the silencing of gene transcription and the histone-to-protamine replacement that controls chromatin architecture of maturing sperm cells, and pinpoints a novel role of the dopaminergic system in the regulation of male germ cells reprogramming.

Supplemental digital content is available in the text. Introduction: The purpose of this study was to determine the effect of growth restriction on the biological regulation of physical activity. Methods: Using a cross-fostering, protein-restricted nutritive model, mice were growth-restricted during either gestation (GUN; N = 3 litters) or postnatal life (PUN; N = 3 litters). At 21 d of age, all mice pups were weaned and fed a nonrestrictive healthy diet for the remainder of the study. At 45 d of age, mice were individually housed in cages with free moving running wheels to assess physical activity engagement. At day 70, mice were euthanized, and the nucleus accumbens was analyzed for dopamine receptor 1 expression. Skeletal muscle fiber type and cross-sectional area of the soleus, extensor digitorom longus, and diaphragm were analyzed by immunohistochemistry. The soleus from the other hindleg was evaluated for calsequestrin 1 and annexin A6 expression. Results: The PUN female mice (15,365 ± 8844 revolutions per day) had a reduction (P = 0.0221) in wheel revolutions per day as compared with the GUN (38,667 ± 8648 revolutions per day) and CON females (36,421.0 ± 6700 revolutions per day). The PUN female mice also expressed significantly higher dopamine receptor 1 compared (P = 0.0247) to the other groups. The PUN female soleus had a higher expression of calsequestrin 1, along with more type IIb fibers (P = 0.0398). Conclusions: Growth restriction during lactation reduced physical activity in female mice by reducing the central drive to be active and displayed a more fatigable skeletal muscle phenotype. [ABSTRACT FROM AUTHOR]

Increasing evidence shows changes in gut microbiota composition in association with psychiatric disorders, including anxiety and depression. Moreover, it has been reported that perturbations in gut microbe diversity and richness influence serotonergic, GABAergic, noradrenergic, and dopaminergic neurotransmission. Among these, dopamine is regarded as a main regulator of cognitive functions such as decision making, attention, memory, motivation, and reward. In this work, we will highlight findings that link alterations in intestinal microbiota and dopaminergic neurotransmission, with a particular emphasis on the mesocorticolimbic circuit, which is involved in reward to natural reinforcers, as well as abuse substances. For this, we reviewed evidence from studies carried out on germ-free animals, or in rodents subjected to intestinal dysbiosis using antibiotics, and also through the use of probiotics. All this evidence strongly supports that the microbiota-gut-brain axis is key to the physiopathology of several neuropsychiatric disorders involving those where dopaminergic neurotransmission is compromised. In addition, the gut microbiota appears as a key player when it comes to proposing novel strategies to the treatment of these psychiatric conditions. [ABSTRACT FROM AUTHOR]

Early-life adversity (ELA) represents a major risk factor for the development of behavioral dysfunctions and mental disorders later in life. On the other hand, dependent on type, time point, and duration, ELA exposure can also induce adaptations, which result in better stress coping and resilience later in life. Guided by the hypothesis that chronic exposure to ELA results in dysfunctional brain and behavior, whereas short exposure to ELA may result in resilience, the behavioral and neurobiological consequences of long-term separation stress (LTSS) and short-term separation stress (STSS) were compared in a mouse model for ELA. In line with our hypothesis, we found that LTSS induced depressive-like behavior, whereas STSS reduced depressive-like behavioral symptoms. We then tested the hypothesis that the opposite behavioral outcomes of the two stress paradigms may be mediated by functional, epigenetically regulated changes of dopaminergic modulation in the hippocampal formation. We found that STSS exposure elevated dopamine receptor D1 (DRD1) gene expression and decreased gene expression of its downstream modulator DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein), which was paralleled by decreased H3 acetylation at its gene promoter region. In contrast, LTSS elevated DARPP-32 gene expression, which was not paralleled by changes in histone acetylation and DRD1 gene expression. These findings indicate that short- and long-term neonatal exposure to ELA induces changes in dopaminergic molecular pathways, some of which are epigenetically regulated and which either alleviate or aggravate depressive-like symptoms later in life. [ABSTRACT FROM AUTHOR]

Dopamine receptor 1 (DR) plays an essential role in regulating respiratory activity in mammals, however, little is known about how this receptor acts to modulate the basic respiratory rhythmogenesis. Here, by simultaneously recording the discharge activities of biphasic expiratory (biphasic E) neurons/inspiratory (I) neurons and the XII nerve rootlets from brainstem slices, we found that the application of DR agonist cis-(±)-1-(aminomethyl)-3,4-dihydro-3-phenyl-1 H-2-benzopyran-5,6-diolhydrochloride (A68930, 5 μM), or forskolin, an intracellular cAMP-increasing agent, substantially decreased respiratory cycle and expiratory time of both types of neurons, and elevated the integral amplitude and frequency of XII nerve rootlets discharge. These changes were reversed by subsequent application of their antagonists SCH-23390 and Rp-Adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt hydrate (Rp-cAMPS), respectively. Importantly, after pretreatment with Rp-cAMPS, the effects of A68930 in both types of neurons were blocked, suggestive of a cAMP-dependent action of A68930. Thus, the current study indicates that DR may modulate basic breathing rhythmogenesis via cAMP-dependent mechanisms. [ABSTRACT FROM AUTHOR]

Primary cilia are nearly ubiquitous cellular appendages that provide important sensory and signaling functions. Ciliary dysfunction underlies numerous human diseases, collectively termed ciliopathies. Primary cilia have distinct functions on different cell types and these functions are defined by the signaling proteins that localize to the ciliary membrane. Neurons throughout the mammalian brain possess primary cilia upon which certain G protein-coupled receptors localize. Yet, the precise signaling proteins present on the vast majority of neuronal cilia are unknown. Here, we report that dopamine receptor 1 (D1) localizes to cilia on mouse central neurons, thereby implicating neuronal cilia in dopamine signaling. Interestingly, ciliary localization of D1 is dynamic, and the receptor rapidly translocates to and from cilia in response to environmental cues. Notably, the translocation of D1 from cilia requires proteins mutated in the ciliopathy Bardet-Biedl syndrome (BBS), and we find that one of the BBS proteins, Bbs5, specifically interacts with D1. [ABSTRACT FROM AUTHOR]

Abstract: Motor activity is a key component in many behavioral tests. To assess the relationship between aging and activity, we recorded motor activity for 72 consecutive hours for C57BL/6J (B6J), BALB/c, AKR/J, senescence-accelerated mouse prone 6 (SAMP6), and senescence-accelerated mouse resistant 1 (SAMR1) strains at the ages of 6 and 12 months. Further, to examine whether the dopamine receptor 1 (D1) signaling system is associated with the age-related alteration of activity, we evaluated the motor activity of the mice treated with SKF82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide), a D1 agonist. Twelve-month-old B6J showed higher activity on day 1 and higher D1 sensitivity than 6-month-old mice. Twelve-month-old BALB/c showed higher activity on day 3 and a slightly lower threshold of D1 than 6-month-old mice. Twelve-month-old AKR/J, SAMR1 and SAMP6 strains showed lower motor activity than 6-month-old mice. The D1 sensitivities in 12-month-old AKR/J and SAMR1 were similar to those of corresponding 6-month-old mice, whereas the D1 sensitivity of 12-month-old SAMP6 was significantly lower than that of 6-month-old SAMP6. SKF82958 significantly increased the motor activity of 6-month-old SAMP6 compared with age-matched, AKR/J and SAMR1. Our results indicate that D1 contributes substantially to the age-related increase of activity in B6J, but not to that in BALB/c. In AKR/J, SAMR1, and SAMP6, an age-related decrease of activity was observed. The contribution of D1 to this appeared to be small in AKR/J and SAMR1, but substantial in SAMP6. Thus, the contribution of D1 to age-related changes of motor activity is strongly strain-dependent. [Copyright &y& Elsevier]

Paternal environmental perturbations, including cocaine intake, can affect the development and behavior of the offspring through epigenetic inheritance. However, the mechanism by which cocaine alters the male germ cells epigenome is almost unexplored. Here, we report that cocaine-treated male mice showed alterations on specific histone post-translational modifications (PTMs) including increased silent chromatin marks H3K9me3 and H3K27me3 and decreased active enhancer and promoter marks H3K27ac and H3K4me3 in isolated germ cells. Also, cocaine increased H3K9ac and H4K16ac levels, involved in the replacement of histones by protamines that take place at round spermatid stage. Cocaine also altered histones H3/H4 epigenetic enzymes by increasing acetyltransferase KAT8/MOF, deacetylase SIRT1 and methyltransferase KMT1C/G9A, and decreasing deacetylases HDAC1/2 and demethylase KDM1A/LSD1 protein levels. Moreover, a pre-treatment with dopamine receptor 1 (DRD1) antagonist SCH23390 (SCH) blocked cocaine effects on H3K4me3, H3K27me3, and H4K16ac epigenetic marks. Interestingly, treatment with SCH-only was able to modify most of the histone marks tested here, pointing to a dopamine role in controlling histone PTMs in germ cells. Taken together, our data suggest a key role for DRD1 in mediating cocaine-triggered epigenetic modifications related to the silencing of gene transcription and the histone-to-protamine replacement that controls chromatin architecture of maturing sperm cells, and pinpoints a novel role of the dopaminergic system in the regulation of male germ cells reprogramming., (Copyright © 2020 González, Gancedo, Janeir Garazatua, Roldán, Vitullo and González.)