Noradrenergic Regulation of the Medial Prefrontal Cortex Mediates Stress Coping in Postpartum Female Mice.

The prevalence of depression in women increases during the postpartum period. We previously reported that subchronic exposure to social stress decreased passive coping in postpartum female mice. This study aimed to investigate whether noradrenaline regulation might regulate coping styles in mice. We first determined whether a different type of stress, subchronic physical stress, decreases passive coping in postpartum females. Postpartum female, virgin female, and male mice were exposed to subchronic restraint stress (restraint stress for 4 h for 5 consecutive days). Subchronic restraint stress decreased passive coping in postpartum females but not in virgin females and males in the forced swim and tail suspension tests. We next examined the neuronal mechanism by which subchronic stress decreases passive coping in postpartum female mice. Neuronal activity and expression of noradrenergic receptors in the medial prefrontal cortex (mPFC) were analyzed using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction, respectively. The mPFC was manipulated using chemogenetics, knockdown, or an α2A adrenergic receptor (AR) antagonist. Immunohistochemistry revealed that subchronic restraint stress increased glutamatergic neuron activation in the mPFC via forced swim stress and decreased α2A AR expression in postpartum females. Chemogenetic activation of glutamatergic neurons in the mPFC, knockdown of α2AAR in the mPFC, and the α2A AR receptor antagonist atipamezole treatment decreased passive coping in postpartum females. Subchronic restraint stress decreased passive coping in postpartum females by increasing glutamatergic neuron activity in the mPFC through α2A AR attenuation. The noradrenergic regulation of the mPFC may be a new target for treating postpartum depression.

Potential Role of Pig UCP3 in Modulating Adipocyte Browning via the Beta-Adrenergic Receptor Signaling Pathway.

Adipose tissue plays an important role in regulating body temperature and metabolism, with white adipocytes serving as storage units for energy. Recent research focused on the browning of white adipocytes (beige adipocytes), causing thermogenesis and lipolysis. The process of browning is linked to the activation of uncoupling protein (UCP) expression, which can be mediated by the ß3 adrenergic receptor pathway. Transcriptional factors, such as peroxisome proliferator activated receptor γ (PPARγ) and PPARγ coactivator 1 alpha, play vital roles in cell fate determination for fat cells. Beige adipocytes have metabolic therapeutic potential to combat diseases such as obesity, diabetes mellitus, and dyslipidemia, owing to their significant impact on metabolic functions. However, the molecular mechanisms that cause the induction of browning are unclear. Therefore, research using animal models and primary culture is essential to provide an understanding of browning for further application in human metabolic studies. Pigs have physiological similarities to humans; hence, they are valuable models for research on adipose tissue. This study demonstrates the browning potential of pig white adipocytes through primary culture experiments. The results show that upregulation of UCP3 gene expression and fragmentation of lipid droplets into smaller particles occur due to isoproterenol stimulation, which activates beta-adrenergic receptor signaling. Furthermore, PPARγ and PGC-1α were found to activate the UCP3 promoter region, similar to that of UCP1. These findings suggest that pigs undergo metabolic changes that induce browning in white adipocytes, providing a promising approach for metabolic research with potential implications for human health. This study offers valuable insights into the mechanism of adipocyte browning using pig primary culture that can enhance our understanding of human metabolism, leading to cures for commonly occurring diseases.

Locus Coeruleus-Noradrenergic Neurons Regulate Stress Coping During Subchronic Exposure to Social Threats: A Characteristic Feature in Postpartum Female Mice.

Stress-coping strategies have been implicated in depression. The control of stress coping may improve the symptom and higher prevalence of depression during the postpartum period in women. However, the neuronal mechanisms underlying stress coping remain to be fully elucidated in postpartum women. In this study, we examined how locus coeruleus-noradrenergic (LC-NA) neurons, which have been associated with both stress coping and depression, regulate changes in coping style induced by subchronic exposure to unfamiliar male mice as a social threat in postpartum female mice. In contrast to virgin females, dams exposed to unfamiliar males daily for four consecutive days showed reduced immobility duration in the forced swim test, indicating that exposure to unfamiliar males decreased passive stress coping in dams. Exposure to unfamiliar males also decreased sucrose palatability in the sucrose preference test and suppressed the crouching behavior in the maternal care test but did not affect anxiety-like behavior in the hole-board test in dams. In fiber photometry analyses, LC-NA neurons showed differential activity between dams and virgin females in response to unfamiliar males. Chemogenetic inhibition of LC-NA neurons during exposure to unfamiliar males prevented the social threat-induced decrease in immobility duration in the forced swim test in dams. Furthermore, inhibition or activation of LC-NA neurons exacerbated crouching behavior in dams. These results indicate that LC-NA neurons regulate the social threat-induced decrease in passive stress coping and relieve social threat-induced inhibition of maternal care in postpartum female mice.

Glutamatergic neurons from the medial prefrontal cortex to the dorsal raphe nucleus regulate maternal aggression in lactating mice.

Glutamatergic signals in the dorsal raphe nucleus (DRN) regulate maternal aggression and care in mice. We examined whether glutamatergic input from the medial prefrontal cortex (mPFC) to the DRN might regulate maternal aggression and care in mice. In the maternal aggression test, each dam was exposed to an identical intruder male twice for 5 min, 60 min apart. During the latter trial (opt trial), the terminals of glutamatergic neurons from the mPFC to the DRN were manipulated using optogenetic techniques. Compared to the former trial (pre-opt trial), the inhibition of glutamatergic input in the opt trial decreased bite frequency and prevented the shortening of biting latency. In contrast, the activation of glutamatergic input at 5 Hz increased the biting frequency. Meanwhile, the activation of glutamatergic input at 1, 10, and 20 Hz prevented the shortening of biting latency without affecting biting frequency. In the maternal care test, activation of glutamatergic input at 5 Hz did not affect maternal care. Our results suggest that glutamatergic neurons from the mPFC to the DRN differently regulate maternal aggression, depending on temporal patterns of their activation, and that the glutamatergic signals that enhance maternal aggression are not involved in the regulation of maternal care.

Regulation of maternal care by corticotropin-releasing factor receptors in the dorsal raphe nucleus in mice.

We previously reported that the dorsal raphe nucleus (DRN) was involved in the regulation of maternal care in lactating female mice. The DRN receives multiple innervations from a variety of the brain regions. Corticotropin-releasing factor (CRF) Type 1 and Type 2 receptors are distributed in the DRN. Both receptors have been implicated in regulating negative aspects including stress, fear, and anxiety. However, it remains unknown how CRF receptors in the DRN regulate maternal care. In the present study, we investigated how CRF receptors in the DRN is involved in regulating maternal care in lactating female mice. Injection of antalarmin or antisauvagine-30, which is an antagonist of CRF Type 1 or Type 2 receptor, respectively, into the DRN increased the latency to retrieving pups into the nest and to crouching over pups, and decreased the duration of crouching over pups, indicating that blockage of CRF receptor signaling in the DRN decreased maternal care. Each treatment did not affect anxiety-related behaviors, which were assayed using the hole-board test. These results suggest that CRF receptor signaling in the DRN positively regulates maternal care in lactating female mice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Investigation of the factors that induce maternal aggression towards juveniles among several mouse strains.

Maternal care and aggression are representative of maternal behavior among lactating female mice. Even neonates and juveniles, who are not biological offspring, can induce maternal care and aggression in dams. Here, we investigated the factors that induce maternal aggression through exposure to juvenile mice. We first addressed the role of intruder age on the induction of maternal aggression in dams. BALB/c dams displayed attacking behavior towards 14-day-old C57BL/6J male intruders. Consumption of food pellets during the weaning period was unlikely to affect the induction of attacking behavior, as the intruders reared by breastfeeding, without food pellets, induced intensive attacking behavior in dams. Next, we compared the intruder-mediated induction of attacking behavior through different mouse strains. Specifically, BALB/c intruders induced a lower level of attacking behavior in BALB/c or ICR dams, compared to the other strains tested. However, BALB/c intruders induced intense attacking behavior in C57BL/6N dams, indicating that the occurrence of attacking behavior is dependent on the strains of dams as well as intruders. A cross-fostering experiment highlighted that the rearing by an original mother was required for C57BL/6J juveniles to induce attacking behavior. In contrast, BALB/c intruders may emit an inhibitory factor that limits attacking behavior. We finally explored which parts of the body emit these aggression-inducible signals. Removal of body hair around the proximal tail of the intruders significantly decreased the attacking behavior of dams, demonstrating that chemical cues, namely pheromones, attached to the body hair around the proximal tail may be essential for inducing attacking behavior in dams.

Oxytocin in the dorsal raphe nucleus antagonizes the inhibition of maternal care induced by food deprivation.

Lactation is indispensable for the pup's survival, but is considered a survival burden in dams under negative energy conditions. In the present study, we tested our hypothesis that oxytocin may facilitate energy investment to pups through behavioral control as well as milk ejection. Maternal care was observed in dams at 3 h but not 8 h after food deprivation. We investigated whether oxytocin in the dorsal raphe nucleus (DRN), which is involved in energy state-dependent regulation of maternal care, regulates maternal care. For this purpose, 2-pmol L368899, an oxytocin receptor antagonist, was injected into the DRN; after treatment, maternal care was inhibited in the dams with 3-h fasting, but not in the fed dams. In contrast, recovery of maternal care was observed in the dams with 8-h fasting who underwent 100-pmol oxytocin injection at the DRN. These results indicate that oxytocin in the DRN is required for displaying maternal behavior under fasting conditions, but not under fed conditions. Next, we investigated the site of oxytocin release. Presentation of pups decreased the oxytocin immunoreactivity at the paraventricular nucleus (PVN) of the hypothalamus in the 3-h-fasted dams, but not in the fed or 8-h-fasted dams. No change of the serum oxytocin level was observed. Few oxytocin-positive neurons projecting from the PVN to the DRN were detected through labeling with the retrograde tracer fluorogold. Oxytocin secreted at the PVN, which reaches the DRN, but not released as a hormone or neurotransmitter may mediate maternal care under food-restricted conditions.

Selective neuronal vulnerability is involved in cerebellar lesions of Guinea pigs infected with bovine spongiform encephalopathy (BSE) prions: Immunohistochemical and electron microscopic investigations.

The cerebellar lesions of bovine spongiform encephalopathy (BSE)-infected guinea pigs were characterized as severe atrophy of the cerebellar cortex associated with the loss of granule cells, decrease in the width of the molecular layer, and intense protease-resistant prion protein (PrPSc ) accumulations that are similar to cerebellar lesions in kuru and the VV2 type of sporadic Creutzfeldt-Jakob disease. The aim of this study is to assess the relationships between the distribution and localization of PrPSc and synapses expressing neurotransmitter transporters in order to reveal the pathogenesis of the disease. We used cell-type-specific immunohistochemical makers recognizing glutamatergic and γ-aminobutylic acid (GABA)ergic terminals to identify terminals impaired with PrPSc accumulations. The distribution of PrPSc accumulations and immunoreactivity of synaptic vesicles were studied throughout the neuroanatomical pathways in cerebellar lesions. Time course study demonstrated that PrPSc accumulation showed a tendency to spread from granular layer to molecular layer. The immunoreactivity of vesicular glutamate transporter 1 (VGluT1) was localized in axon terminals of cerebellar granule cells, and decreased in association with the severity of PrPSc accumulations and loss of granule cells. Immunoreactivities of vesicular glutamate transporter 2 (VGluT2) and vesicular GABA transporter (VGAT) that exist in axon terminals of inferior olivary neurons and GABAergic synapses of Purkinje cells, respectively, were preserved well in these lesions. In brainstem, VGluT1 immunoreactivity decreased selectively in pontine nuclei that are a component of the pontocerebellar pathway, although other neurotransmitter immunoreactivities were preserved well. Our findings suggest that the selective loss of VGluT1-immunoreactive synapses subsequent to PrPSc accumulations can contribute to the pathogenesis of cerebellar lesions of BSE-infected guinea pigs.

Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson's Disease.

Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.

Glutamatergic Signals in the Dorsal Raphe Nucleus Regulate Maternal Aggression and Care in an Opposing Manner in Mice.

Lactating female mice nurture their pups and attack intruders in their territory. When an intruder invades a dam's territory, she needs to switch her behavior from care to aggression to protect her pups and territory. Although the neuronal mechanisms underlying each distinct behavior have been studied, it is unclear how these behaviors are displayed alternatively. The dorsal raphe nucleus (DRN) regulates both nurturing and aggressive behaviors. In the present study, we examined whether the DRN is involved in regulating alternative display of maternal care and aggression. We first examined neuronal activity in the medial prefrontal cortex (mPFC) and lateral habenula (LHb), which send glutamatergic input to the DRN, in dams by injecting Fluorogold, a retrograde tracer, into the DRN. The number of c-Fos- and Fluorogold-positive neurons in the mPFC and LHb increased in the dams that displayed biting behavior in response to an intruder, but remained unchanged in the dams that displayed nurturing behavior. Injections of N-methyl-d-aspartic acid (NMDA) receptor antagonists or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists into the DRN inhibited biting behavior but not nurturing behavior. In contrast, injections of NMDA or AMPA into the DRN inhibited nurturing behavior. These results suggest that glutamatergic signals in the DRN, which may originate from the mPFC and/or LHb, regulate the preferential display of biting behavior over nurturing behavior in dams.

The Accessory Olfactory System Facilitates the Recovery of the Attraction to Familiar Volatile Female Odors in Male Mice.

Odors in female mice induce sexual arousal in male mice. Repeated exposure to female odors attenuates male attraction, which recovers when the odors are removed. The neuronal mechanisms for the recovery of male attraction have not been clarified. In this study, we examined how olfactory systems are involved in the recovery of male attraction to female odors following habituation in mice. Presentation with volatile female odors for 5 min induced habituation in males. To evaluate male attraction to familiar volatile female odors, we measured the duration for investigating volatile female odors from the same female mouse, which was presented twice for 5 min with 1-, 3-, or 5-min interval. Intranasal irrigation with ZnSO4 solution almost completely suppressed investigating behavior, indicating that the main olfactory system is indispensable for inducing the attraction to volatile female odors. In contrast, removal of the vomeronasal organ, bilateral lesions of the accessory olfactory bulb (AOB), or pharmacological blockage of neurotransmission in the AOB did not affect the investigation time at the first odor presentation. However, each one of the treatments decreased the investigation time in the second presentation, compared to that in the first presentation, at longer intervals than control treatment, indicating that the disturbance of neurotransmission in the accessory olfactory system delayed the recovery of the attraction attenuated by the first presentation. These results suggest that the accessory olfactory system facilitates the recovery of the attraction to familiar volatile female odors in male mice.

Rolipram improves facilitation of contextual fear extinction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.

Cognitive impairment often occurs in Parkinson's disease (PD), but the mechanism of onset remains unknown. Recently, we reported that PD model mice produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show facilitation of hippocampal memory extinction, which may be the cause of cognitive impairment in PD. When we examined the cAMP/CREB signaling in the hippocampus, decreased levels of cAMP and phosphorylated CREB were observed in the dentate gyrus (DG) of MPTP-treated mice. Administration of rolipram improved the memory deficits with concomitant recovery of cAMP and phosphorylated CREB levels, suggesting that reduced cAMP/CREB signaling in the DG leads to cognitive impairment in MPTP-treated mice.

A novel neuropeptide Y neuronal pathway linking energy state and reproductive behavior.

Animals consume energy for reproduction, as well as survival. Excess or insufficient energy investment into reproduction, respectively, threatens the survival of parents or leads to the failure of reproduction. Management of energy consumption in reproduction is important, not only for the success of the process, but also for the survival of the parents. Reproductive behaviors, such as mating and parental behavior, are indispensable for achieving each event of reproduction including gametogamy, parturition, and lactation. Therefore, reproductive behavior is one of the important factors in managing energy consumption for reproduction. Orexigenic and anorexigenic molecules in the hypothalamus have been implicated in the regulation of reproductive functions. An orexigenic neuropeptide, neuropeptide Y (NPY), has been also implicated in the regulation of both reproduction and energy state of animals. In this review, we will first summarize the neuronal mechanism for regulating reproductive functions by orexigenic and anorexigenic molecules in the hypothalamus. Second, we will focus on the NPY neuronal pathways regulating reproductive behavior in the intra- and extra-hypothalamic brain areas. We will highlight the NPY neuronal pathway from the arcuate nucleus to the dorsal raphe nucleus as a novel extra-hypothalamic pathway for energy state-dependent regulation of reproductive behavior. Finally, we will propose a biological significance of the extra-hypothalamic NPY neuronal pathway, which plays an important role in the associative control of feeding and reproductive behaviors.

The effects of unilateral lesion of the tuberomammillary nucleus E2 sub-region on nocturnal feeding and related behaviors in mice.

AIMS: Bilateral lesions of the mesencephalic trigeminal sensory nucleus (Me5), which receives histaminergic neurons from the tuberomammillary nucleus (TMN), alter nocturnal feeding and related behaviors in mice, concomitant with a decrease in orexin mRNA level in the perifornical area (PFA) during the dark phase. Therefore, we investigated the neuronal input to the TMN from the Me5, as well as the effects of TMN lesions on the circadian profiles of feeding and related behaviors. MAIN METHODS: We examined the presence of neurons projecting from the Me5 to the TMN by direct injection of a retrograde tracer, Fluorogold, into the TMN E2 sub-region (TMN-E2). We also assessed feeding, drinking, and locomotion for 24h using an automated feeding behavior measurement apparatus, and analyzed the hypothalamic orexin mRNA levels in both TMN-lesion and sham-operated mice. KEY FINDINGS: The presence of neuronal projections from the Me5 to the TMN-E2 was confirmed. A decrease in food and water intake and locomotion during the latter half of the dark phase was delayed in TMN-lesion but not sham-operation mice. Further, orexin mRNA expression levels were higher in both the PFA and lateral hypothalamus area (LHA) in TMN-E2-lesion mice relative to control mice, during the early half of the dark phase compared with the light phase. SIGNIFICANCE: Our results suggest that histaminergic neurons in the TMN-E2 receive signals from the Me5 that modulate a switch from dark to light phase feeding and related behaviors, which in turn may be regulated by orexin neurons in the PFA and/or LHA.

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection.

Changes in neurotransmitter levels and expression of immediate early genes in brain of mice infected with Neospora caninum.

Neospora caninum is an obligate intracellular parasite that causes neurological disorders in dogs and cattle. The majority of host animals are asymptomatic at the chronic stage of infection. However, it remains unclear whether cerebral function is normal in asymptomatic animals. In this study, mice were infected with N. caninum (strain Nc-1) and their brains were examined to understand changes in cerebral function at the chronic stage of infection. Mice infected with N. caninum showed impaired locomotor activity, but no differences in clinical symptoms were observed. In the brains of infected mice, parasites were distributed throughout the brain and histological lesions were observed everywhere except for the cerebellum. Expression levels of proinflammatory cytokines, interferon-gamma and tumour necrosis factor-alpha, were highly upregulated in several brain regions of infected mice. Additionally, the level of neurotransmitters glutamate, glycine, gamma-aminobutyric acid, dopamine and 5-hydroxytryptamine, were altered in infected mice compared with those of uninfected mice. Interestingly, the expression levels of immediately early genes, c-Fos and Arc, in the brain of infected mice were lower than those of in uninfected mice. Our findings may provide insight into neurological disorders associated with N. caninum infection.

Serotonin modulates the dehydration-induced changes in tolerance for bitter water.

Drinking behavior is regulated by endogenous factors such as the hydration condition of animals and exogenous factors such as the taste of ingested fluids. These factors have been suggested to interact with each other via serotonergic (5-HT) signaling to regulate drinking behavior. In the present study, we examined how dehydration affects the intake of bitter water, which suppresses drinking behavior, via 5-HT signaling. Water deprivation increased water intake for 1h, depending on the duration of water deprivation. The intake of 1mM quinine, which is a bitter tastant, was lower than that of water in mice deprived of water for 24h but not 48 h. We next examined the involvement of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), which contain a large population of 5-HT neurons, in changing tolerance for quinine intake after water deprivation. The intake of quinine following water deprivation for 24h, but not 48 h, increased the number of tryptophan hydroxylase-positive neurons expressing c-Fos in the DRN, but not in the MRN. Moreover, administration of paroxetine, a selective serotonin reuptake inhibitor, decreased the intake of quinine solution, but not water, in mice deprived of water for 48 h, indicating that paroxetine treatment restored the aversion to quinine. These results suggest that unresponsiveness of 5-HT neurons in the DRN may be involved in the dehydration-induced increase in tolerance for bitter water.

Cytoprotective Effects of Lysophospholipids from Sea Cucumber Holothuria atra.

Lysophospholipids are important signaling molecules in animals and metazoan cells. They are widely distributed among marine invertebrates, where their physiological roles are unknown. Sea cucumbers produce unique lysophospholipids. In this study, two lysophospholipids were detected in Holothuria atra for the first time, lyso-platelet activating factor and lysophosphatidylcholine, with nuclear magnetic resonance and liquid chromatography-time-of-flight mass spectrometric analyses. The lipid fraction of H. atra contained lyso-platelet activating factor and lysophosphatidylcholine, and inhibited H2O2-induced apoptosis in the macrophage cell line J774A.1. The antioxidant activity of the lysophospholipid-containing lipid fraction of H. atra was confirmed with the oxygen radical absorbance capacity method. Our results suggest that the lysophospholipids from H. atra are potential therapeutic agents for the inflammation induced by oxidative stress.

Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning.

AIMS: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. MAIN METHODS: We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1mA/2s duration, once, or an intense unconditioned stimulus: 2mA/2s duration, twice), and 24h later, mice were re-exposed to the training context for 3min to determine reconsolidation or 30min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. KEY FINDINGS: Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. SIGNIFICANCE: PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning.

Comparison of c-Fos expression in brain regions involved in maternal behavior of virgin and lactating female mice.

Maternal care is indispensable for the survival of mammalian offspring. Although virgin female mice avoid pups, they actively display maternal behavior after parturition. To determine which brain regions are involved in the qualitative differences observed in the responses of virgin and lactating females to pups, we compared the expression of c-Fos, which is a marker of neuronal activation, in brain regions involved in regulating maternal behavior. Pup presentation increased the number of c-Fos-positive cells in both the ventrotegmental area (VTA) and nucleus accumbens to a greater extent in lactating females than in virgin females. The bed nucleus of striaterminalis (BNST), which innervates VTA neurons to regulate both aversive and rewarding responses, showed increased number of c-Fos-positive cells following pup presentation in virgin females, butnotin lactating females. On the other hand, the number of c-Fos-positive cells in the medial preoptic area (MPOA) increased in both virgin and lactating females. The number of c-Fos-positive cells in lactating females not presented with pups was high and similar to that in virgin females presented with pups. Moreover, c-Fos-positive GABAergicneurons projecting from the MPOA to the BNST was confirmed using a retrograde tracer Fluorogold in lactating females. Our results indicate that constitutive GABAergic modulation projecting from the MPOA may suppress the activity of BNST neurons and prevent avoidance responses to pups in lactating females.