Dysbindin-1A modulation of astrocytic dopamine and basal ganglia dependent behaviors relevant to schizophrenia.

The mechanisms underlying the dichotomic cortical/basal ganglia dopaminergic abnormalities in schizophrenia are unclear. Astrocytes are important non-neuronal modulators of brain circuits, but their role in dopaminergic system remains poorly explored. Microarray analyses, immunohistochemistry, and two-photon laser scanning microscopy revealed that Dys1 hypofunction increases the reactivity of astrocytes, which express only the Dys1A isoform. Notably, behavioral and electrochemical assessments in mice selectively lacking the Dys1A isoform unraveled a more prominent impact of Dys1A in behavioral and dopaminergic/D2 alterations related to basal ganglia, but not cortical functioning. Ex vivo electron microscopy and protein expression analyses indicated that selective Dys1A disruption might alter intracellular trafficking in astrocytes, but not in neurons. In agreement, Dys1A disruption only in astrocytes resulted in decreased motivation and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. These processes might have clinical relevance because the caudate, but not the cortex, of patients with schizophrenia shows a reduction of the Dys1A isoform. Therefore, we started to show a hitherto unknown role for the Dys1A isoform in astrocytic-related modulation of basal ganglia behavioral and dopaminergic phenotypes, with relevance to schizophrenia.

Microglia control glutamatergic synapses in the adult mouse hippocampus.

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1-/- mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.

Synaptic alterations as a neurodevelopmental trait of Duchenne muscular dystrophy.

Dystrophinopaties, e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy and X-linked dilated cardiomyopathy are inherited neuromuscular diseases, characterized by progressive muscular degeneration, which however associate with a significant impact on general system physiology. The more severe is the pathology and its diversified manifestations, the heavier are its effects on organs, systems, and tissues other than muscles (skeletal, cardiac and smooth muscles). All dystrophinopaties are characterized by mutations in a single gene located on the X chromosome encoding dystrophin (Dp427) and its shorter isoforms, but DMD is the most devasting: muscular degenerations manifests within the first 4 years of life, progressively affecting motility and other muscular functions, and leads to a fatal outcome between the 20s and 40s. To date, after years of studies on both DMD patients and animal models of the disease, it has been clearly demonstrated that a significant percentage of DMD patients are also afflicted by cognitive, neurological, and autonomic disorders, of varying degree of severity. The anatomical correlates underlying neural functional damages are established during embryonic development and the early stages of postnatal life, when brain circuits, sensory and motor connections are still maturing. The impact of the absence of Dp427 on the development, differentiation, and consolidation of specific cerebral circuits (hippocampus, cerebellum, prefrontal cortex, amygdala) is significant, and amplified by the frequent lack of one or more of its lower molecular mass isoforms. The most relevant aspect, which characterizes DMD-associated neurological disorders, is based on morpho-functional alterations of selective synaptic connections within the affected brain areas. This pathological feature correlates neurological conditions of DMD to other severe neurological disorders, such as schizophrenia, epilepsy and autistic spectrum disorders, among others. This review discusses the organization and the role of the dystrophin-dystroglycan complex in muscles and neurons, focusing on the neurological aspect of DMD and on the most relevant morphological and functional synaptic alterations, in both central and autonomic nervous systems, described in the pathology and its animal models.

Spatiotemporal Variation in Hatching Success and Nestling Sex Ratios Track Rapid Movement of a Songbird Hybrid Zone.

AbstractHybridization often occurs at the parapatric range interface between closely related species, but fitness outcomes vary: hybrid offspring exhibit diverse rates of viability and reproduction compared with their parental species. The mobile hybrid zone between two chickadee congeners (Poecile atricapillus × Poecile carolinensis) has been well studied behaviorally and genetically, but the viability of hybrids and the underlying mechanisms contributing to hybrid fitness have remained unclear. To better characterize the fitness costs of hybridization in this system, we analyzed 21 years of data from four sites, including more than 1,400 breeding attempts by the two species, to show that rates of hatching success changed substantially as the zone of hybridization moved across the landscape. Admixture-associated declines in hatching success correlated with reduced proportions of heterogametic (female) offspring, as predicted by Haldane's rule. Our data support an underlying mechanism implicating genetic admixture of the homogametic (male) parent as the primary determinant of offspring sex ratio, via incompatibilities on the hemizygous Z chromosome. Our long-term study is the first to directly measure changes in fitness costs as a vertebrate hybrid zone moves, and it shows that changes in these costs are a way to track the distribution of a hybrid zone across the landscape.

Dopamine-mediated immunomodulation affects choroid plexus function.

Immune system alterations have been implicated in various dopamine-related disorders, such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder (ADHD). How immunity might be influenced by dopaminergic dysfunction and impact on clinically-relevant behaviors is still uncertain. We performed a peripheral and cerebral immunophenotyping in mice bearing dopaminergic alteration produced by genetic liability (hypofunction of the dopamine transporter DAT) and psychostimulant (amphetamine) administration. We found that DAT hypofunction influences immune tolerance by increasing functional Tregs and adrenomedullin levels in the thymus and spleen, while reducing microglia activation and infiltration of brain monocyte-derived macrophages (mo-MΦ). Remarkably, both DAT hypofunction and amphetamine treatment are associated with a weaker activation of the choroid plexus (CP) gateway. Conversely, amphetamine reactivated the CP in the setting of DAT hypofunction, paralleling its paradoxical ADHD-relevant behavioral effects. These findings add new knowledge on dopaminergic immunopharmacology and support the immunomodulation of CP functionality as a promising therapeutic strategy for neurodevelopmental and psychiatric disorders.

An Integrated Framework for Environmental Multi-Impact Spatial Risk Analysis.

Quantitative risk analysis is being extensively employed to support policymakers and provides a strong conceptual framework for evaluating decision alternatives under uncertainty. Many problems involving environmental risks are, however, of a spatial nature, i.e., containing spatial impacts, spatial vulnerabilities, and spatial risk-mitigation alternatives. Recent developments in multicriteria spatial analysis have enabled the assessment and aggregation of multiple impacts, supporting policymakers in spatial evaluation problems. However, recent attempts to conduct spatial multicriteria risk analysis have generally been weakly conceptualized, without adequate roots in quantitative risk analysis. Moreover, assessments of spatial risk often neglect the multidimensional nature of spatial impacts (e.g., social, economic, human) that are typically occurring in such decision problems. The aim of this article is therefore to suggest a conceptual quantitative framework for environmental multicriteria spatial risk analysis based on expected multi-attribute utility theory. The framework proposes: (i) the formal assessment of multiple spatial impacts; (ii) the aggregation of these multiple spatial impacts; (iii) the assessment of spatial vulnerabilities and probabilities of occurrence of adverse events; (iv) the computation of spatial risks; (v) the assessment of spatial risk mitigation alternatives; and (vi) the design and comparison of spatial risk mitigation alternatives (e.g., reductions of vulnerabilities and/or impacts). We illustrate the use of the framework in practice with a case study based on a flood-prone area in northern Italy.

Increased axonal bouton dynamics in the aging mouse cortex.

Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for age-related cognitive decline.

Staying awake--a genetic region that hinders α2 adrenergic receptor agonist-induced sleep.

How external stimuli prevent the onset of sleep has been little studied. This is usually considered to be a non-specific type of phenomenon. However, the hypnotic drug dexmedetomidine, an agonist at α2 adrenergic receptors, has unusual properties that make it useful for investigating this question. Dexmedetomidine is considered to produce an 'arousable' sleep-like state, so that patients or animals given dexmedetomidine become alert following modest stimulation. We hypothesized that it might be more difficult to make mice unconscious with dexmedetomidine if there was a sufficient external stimulus. Employing a motorized rotating cylinder, which provided a continuous and controlled arousal stimulus, we quantitatively measured the ability of such a stimulus to prevent dexmedetomidine loss of righting reflex in two inbred strains of mice (C57BL/6 and 129X1). We found that whereas the C57BL/6 strain required a strong stimulus to prevent dexmedetomidine-induced hypnosis, the 129X1 strain stayed awake even with minimal stimuli. Remarkably, this could be calibrated as a simple threshold trait, i.e. a binary 'yes-no' response, which after crossing the two mouse strains behaved as a dominant-like trait. We carried out a genome-wide linkage analysis on the F2 progeny to determine if the ability of a stimulus to prevent dexmedetomidine hypnosis could be mapped to one or more chromosomal regions. We identified a locus on chromosome 4 with an associated Logarithm of Odds score exceeding the pre-established threshold level. These results show that complex traits, such as the ability of a stimulus to reverse drug-induced hypnosis, may have precise genetic determinants.

Ventral striatal plasticity and spatial memory.

Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs long-term spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation.

Somatostatin interneurons in the prefrontal cortex control affective state discrimination in mice.

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we show a differential activation of medial PFC (mPFC) neurons during social exploration that depends on the affective state of the conspecific. Optogenetic manipulations revealed a double dissociation between the role of interneurons in social cognition. Specifically, inhibition of mPFC somatostatin (SOM+), but not of parvalbumin (PV+) interneurons, abolishes affective state discrimination. Accordingly, synchronized activation of mPFC SOM+ interneurons selectively induces social discrimination. As visualized by in vivo single-cell microendoscopic Ca2+ imaging, an increased synchronous activity of mPFC SOM+ interneurons, guiding inhibition of pyramidal neurons, is associated with affective state discrimination. Our findings provide new insights into the neurobiological mechanisms of affective state discrimination.

Full lifetime perspectives on the costs and benefits of lay-date variation in tree swallows.

Animals must balance various costs and benefits when deciding when to breed. The costs and benefits of breeding at different times have received much attention, but most studies have been limited to investigating short-term season-to-season fitness effects. However, breeding early, versus late, in a season may influence lifetime fitness over many years, trading off in complex ways across the breeder's lifespan. In this study, we examined the complete life histories of 867 female tree swallows (Tachycineta bicolor) breeding in Ithaca, New York, between 2002 and 2016. Earlier breeders outperformed later breeders in short-term measures of reproductive output and offspring quality. Though there were weak indications that females paid long-term future survival costs for breeding early, lifetime fledgling output was markedly higher overall in early-breeding birds. Importantly, older females breeding later in the season did not experience compensating life history advantages that suggested an alternative equal-fitness breeding strategy. Rather, most or all of the swallows appear to be breeding as early as they can, and differences in lay dates appear to be determined primarily by differences in individual quality or condition. Lay date had a significant repeatability across breeding attempts by the same female, and the first lay date of females fledged in our population was strongly influenced by the first lay date of their mothers, indicating the potential for ongoing selection on lay date. By examining performance over the entire lifespan of a large number of individuals, we were able to clarify the relationship between timing of breeding and fitness and gain new insight into the sources of variability in this important life history trait.

Understanding others: Emotion recognition in humans and other animals.

Emotion recognition represents the ability to encode an ensemble of sensory stimuli providing information about the emotional state of another individual. This ability is not unique to humans. An increasing number of studies suggest that many aspects of higher order social functions, including emotion recognition, might be present in species ranging from primates to rodents, indicating a conserved role in social animals. The aim of this review is to examine and compare how emotions are communicated and perceived in humans and other animals, with the intent to highlight possible new behavioral approaches and research perspectives. We summarize the evidence from human emotion recognition, and latest advances in the development of nonhuman animal behavioral tests, using or implying the use of this cognitive function. The differential implication of sensory modalities used by animals to communicate and decipher emotional states is also discussed. The opportunity to measure emotion recognition abilities in rodents may allow us to better identify the neural mechanisms mediating this complex function, thus promoting the development of new intervention strategies for several neuropsychiatric disorders characterized by social cognitive dysfunctions.

Acute Administration of URB597 Fatty Acid Amide Hydrolase Inhibitor Prevents Attentional Impairments by Distractors in Adolescent Mice.

The maturation of attentional control during adolescence might influence later functional outcome or predisposition to psychiatric disorders. During adolescence, the cannabinoid system is particularly sensitive to pharmacological challenges, with potential impact on cognitive functions. Here, we used a recently validated five-choice serial reaction time task protocol to test adolescent C57BL/6J mice. We showed that the pharmacological inhibition (by URB597) of the fatty acid amide hydrolase (FAAH), the major enzyme implicated in anandamide degradation, prevented cognitive disruptions induced by distracting cues in adolescent mice. In particular, these protective effects were indicated by increased accuracy and correct responses and decreased premature responses selectively in the distractor trials. Notably, at the relatively low dose used, we detected no effects in other cognitive, motor, or incentive measures nor long-lasting or rebound effects of FAAH inhibition in cognitive functions. Overall, these data provide initial evidence of selective procognitive effects of FAAH inhibition in measures of attentional control in adolescent mice.

Temperate-Tropical Variation in Breeding Synchrony and Extra-Pair Paternity Among New World Tachycineta Swallows.

Extra-pair paternity rates vary markedly across avian taxa, but patterns of variation in this trait have been obscured by a paucity of data on closely related species, especially those spanning broad environmental gradients. Here we compare variation in extra-pair paternity rates among five species in the widespread swallow genus Tachycineta. Rates of extra-pair paternity vary widely in this group, ranging from 13 to 87% of nests having extra-pair young. The inter-specific variation in extra-pair paternity within this small group of closely related swallows has a range equivalent to that found among all Hirundinidae and is close to the range of variation across all birds. Despite theory that predicts extra-pair paternity rates to be explained by latitudinal variation in breeding synchrony our results show that extra-pair paternity rates in this genus do not closely track a latitudinal gradient, as predicted by studies of other life-history traits, and are not explained by differences in breeding synchrony as previously suggested. The genetic mating systems of birds, described by the rates of extra-pair paternity, are connected to all other life-history traits through a complex network of trade-offs with organismal (phylogenetic) and ecological (environmental) factors. Disentangling each of these interactions to understand latitudinal patterns in any given life-history trait remains a daunting task.

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice.

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions.

Effects of intra-accumbens NMDA and AMPA receptor antagonists on short-term spatial learning in the Morris water maze task.

Glutamatergic transmission within the nucleus accumbens (Nac) is considered to subserve the transfer of different types of information from the cortical and limbic regions. In particular, it has been suggested that glutamatergic afferences from the hippocampus and the prefrontal cortex provide the main source of contextual information to the Nac. Accordingly, several authors have demonstrated that the blockade of glutamate receptors within the Nac impairs various spatial tasks. However, the exact role of the different classes of glutamate receptors within the Nac in short-term spatial memory is still not clear. In this study we investigated the involvement of two major classes of glutamate receptors, NMDA and AMPA receptors, within the Nac in the acquisition of spatial information, using the Morris water maze task. Focal injections of the NMDA antagonist, AP-5 (0.1 and 0.15 microg/side), and the AMPA antagonist, DNQX (0.005, 0.01 microg/side), were performed before a massed training phase, and mice were tested for retention immediately after. NMDA and AMPA receptor blockade induced no effect during training. On the contrary, injection of the two glutamatergic antagonists impaired spatial localization during the probe test. These data demonstrate an involvement of the Nac in short-term spatial learning. Moreover, they prove that within this structure the short-term processing of spatial information needs the activation of both NMDA and AMPA receptors.

Life-history variation of a neotropical thrush challenges food limitation theory.

Since David Lack first proposed that birds rear as many young as they can nourish, food limitation has been accepted as the primary explanation for variation in clutch size and other life-history traits in birds. The importance of food limitation in life-history variation, however, was recently questioned on theoretical grounds. Here, we show that clutch size differences between two populations of a neotropical thrush were contrary to expectations under Lack's food limitation hypothesis. Larger clutch sizes were found in a population with higher nestling starvation rate (i.e. greater food limitation). We experimentally equalized clutches between populations to verify this difference in food limitation. Our experiment confirmed greater food limitation in the population with larger mean clutch size. In addition, incubation bout length and nestling growth rate were also contrary to predictions of food limitation theory. Our results demonstrate the inability of food limitation to explain differences in several life-history traits: clutch size, incubation behaviour, parental feeding rate and nestling growth rate. These life-history traits were better explained by inter-population differences in nest predation rates. Food limitation may be less important to life history evolution in birds than suggested by traditional theory.

Co-activation of glutamate and dopamine receptors within the nucleus accumbens is required for spatial memory consolidation in mice.

RATIONALE: The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate-dopamine receptor interactions. OBJECTIVES: The purpose of this study was to examine the effects of intra-accumbens co-administrations of glutamate and DA antagonists on the consolidation of spatial information. METHODS: On day 1, CD1 male mice were placed in an open field containing five different objects and immediately after three sessions of habituation the animals were injected intra-accumbens with either vehicle or low doses of the N-methyl-D: -aspartate (NMDA; AP-5 50 ng/side), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; DNQX 5 ng/side), the D1 (SCH23390 12.5 ng/side) and the D2 (sulpiride 25 ng/side) antagonists that were ineffective alone in disrupting object displacement. Separate groups were then focally injected with a combination of one of the glutamate antagonists with one of the dopamine antagonists. Twenty-four hours later, the ability of mice to discriminate object displacement was assessed. RESULTS: Controls and mice injected with ineffective doses of the NMDA, the AMPA, the D1 or the D2 antagonists were always able to react to the object displacement. On the contrary, the groups administered with the different combinations (AP-5 and SCH23390, AP-5 and sulpiride, DNQX and SCH23390, DNQX and sulpiride) of glutamate and dopamine antagonists did not discriminate the spatial change. CONCLUSIONS: These results demonstrate that glutamate-dopamine receptor interactions within the accumbens are essential for the consolidation process of spatial information.