Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.

BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

Disruption of centrifugal inhibition to olfactory bulb granule cells impairs olfactory discrimination.

Granule cells (GCs) are the most abundant inhibitory neuronal type in the olfactory bulb and play a critical role in olfactory processing. GCs regulate the activity of principal neurons, the mitral cells, through dendrodendritic synapses, shaping the olfactory bulb output to other brain regions. GC excitability is regulated precisely by intrinsic and extrinsic inputs, and this regulation is fundamental for odor discrimination. Here, we used channelrhodopsin to stimulate GABAergic axons from the basal forebrain selectively and show that this stimulation generates reliable inhibitory responses in GCs. Furthermore, selective in vivo inhibition of GABAergic neurons in the basal forebrain by targeted expression of designer receptors exclusively activated by designer drugs produced a reversible impairment in the discrimination of structurally similar odors, indicating an important role of these inhibitory afferents in olfactory processing.

Basal Forebrain Modulation of Olfactory Coding In Vivo.

Sensory perception is one of the most fundamental brain functions, allowing individuals to properly interact and adapt to a constantly changing environment. This process requires the integration of bottom-up and topdown neuronal activity, which is centrally mediated by the basal forebrain, a brain region that has been linked to a series of cognitive processes such as attention and alertness. Here, we review the latest research using optogenetic approaches in rodents and in vivo electrophysiological recordings that are shedding light on the role of this region, in regulating olfactory processing and decisionmaking. Moreover, we summarize evidence highlighting the anatomical and physiological differences in the basal forebrain of individuals with autism spectrum disorder, which could underpin the sensory perception abnormalities they exhibit, and propose this research line as a potential opportunity to understand the neurobiological basis of this disorder.

La percepción sensorial es una de las funciones cerebrales más fundamentales, permitiendo a los individuos interactuar de manera apropiada con el entorno y adaptarse a un ambiente en constante cambio. Este proceso requiere la integración de la actividad neuronal ascendente y descendente, que es mediada por el cerebro basal (BF), una región cerebral que ha sido asociada a una serie de procesos cognitivos, como estados de atención y alerta.En este trabajo revisamos las últimas investigaciones que han utilizado optogenética y registros electrofisiológicos in vivo que han iluminado el rol del BF en el procesamiento olfatorio y la toma de decisiones. Además, resumimos la literatura que destaca las alteraciones fisiológicas y anatómicas del BF de individuos con trastornos del espectro autista, que podrían subyacer las anormalidades en la percepción que presentan, y proponemos esta línea de investigación como una posible oportunidad para entender las bases neurobiológicas de este trastorno.

Neurodevelopment and early pharmacological interventions in Fragile X Syndrome.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading monogenic cause of autism and intellectual disability. For years, several efforts have been made to develop an effective therapeutic approach to phenotypically rescue patients from the disorder, with some even advancing to late phases of clinical trials. Unfortunately, none of these attempts have completely succeeded, bringing urgency to further expand and refocus research on FXS therapeutics. FXS arises at early stages of postnatal development due to the mutation and transcriptional silencing of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1) and consequent loss of the Fragile X Messenger Ribonucleoprotein (FMRP) expression. Importantly, FMRP expression is critical for the normal adult nervous system function, particularly during specific windows of embryogenic and early postnatal development. Cellular proliferation, migration, morphology, axonal guidance, synapse formation, and in general, neuronal network establishment and maturation are abnormally regulated in FXS, underlying the cognitive and behavioral phenotypes of the disorder. In this review, we highlight the relevance of therapeutically intervening during critical time points of development, such as early postnatal periods in infants and young children and discuss past and current clinical trials in FXS and their potential to specifically target those periods. We also discuss potential benefits, limitations, and disadvantages of these pharmacological tools based on preclinical and clinical research.

Microbiota Profile of the Nasal Cavity According to Lifestyles in Healthy Adults in Santiago, Chile.

BACKGROUND: The respiratory microbiome is dynamic, varying between anatomical niches, and it is affected by various host and environmental factors, one of which is lifestyle. Few studies have characterized the upper respiratory tract microbiome profile according to lifestyle. We explored the association between lifestyles and microbiota profiles in the upper respiratory tract of healthy adults. METHODS: We analyzed nasal samples from 110 healthy adults who were living in Santiago, Chile, using 16S ribosomal RNA gene-sequencing methods. Volunteers completed a structured questionnaire about lifestyle. RESULTS: The composition and abundance of taxonomic groups varied across lifestyle attributes. Additionally, multivariate models suggested that alpha diversity varied in the function of physical activity, nutritional status, smoking, and the interaction between nutritional status and smoking, although the significant impact of those variables varied between women and men. Although physical activity and nutritional status were significantly associated with all indexes of alpha diversity among women, the diversity of microbiota among men was associated with smoking and the interaction between nutritional status and smoking. CONCLUSIONS: The alpha diversity of nasal microbiota is associated with lifestyle attributes, but these associations depend on sex and nutritional status. Our results suggest that future studies of the airway microbiome may provide a better resolution if data are stratified for differences in sex and nutritional status.

Regulation of adult neurogenesis by behavior and age in the accessory olfactory bulb.

The vomeronasal system (VNS) participates in the detection and processing of pheromonal information related to social and sexual behaviors. Within the VNS, two different populations of sensory neurons, with a distinct pattern of distribution, line the epithelium of the vomeronasal organ (VNO) and give rise to segregated sensory projections to the accessory olfactory bulb (AOB). Apical sensory neurons in the VNO project to the anterior AOB (aAOB), while basal neurons project to the posterior AOB (pAOB). In the AOB, the largest population of neurons are inhibitory, the granule and periglomerular cells (GCs and PGs) and remarkably, these neurons are continuously born and functionally integrated in the adult brain, underscoring their role on olfactory function. Here we show that behaviors mediated by the VNS differentially regulate adult neurogenesis across the anterior-posterior axis of the AOB. We used immunohistochemical labeling of newly born cells under different behavioral conditions in mice. Using a resident-intruder aggression paradigm, we found that subordinate mice exhibited increased neurogenesis in the aAOB. In addition, in sexually naive adult females exposed to soiled bedding odorized by adult males, the number of newly born cells was significantly increased in the pAOB; however, neurogenesis was not affected in females exposed to female odors. In addition, we found that at two months of age adult neurogenesis was sexually dimorphic, with male mice exhibiting higher levels of newly born cells than females. Interestingly, adult neurogenesis was greatly reduced with age and this decrease correlated with a decrease in progenitor cells proliferation but not with an increase in cell death in the AOB. These results indicate that the physiological regulation of adult neurogenesis in the AOB by behaviors is both sex and age dependent and suggests an important role of newly born neurons in sex dependent behaviors mediated by the VNS.

Expression and distribution of facilitative glucose (GLUTs) and monocarboxylate/H+ (MCTs) transporters in rat olfactory epithelia.

Cell-to-cell metabolic interactions are crucial for the functioning of the nervous system and depend on the differential expression of glucose transporters (GLUTs) and monocarboxylate transporters (MCTs). The olfactory receptor neurons (ORNs) and supporting cells (SCs) of the olfactory epithelium exhibit a marked polarization and a tight morphological interrelationship, suggesting an active metabolic interaction. We examined the expression and localization of MCTs and GLUTs in the olfactory mucosa and found a stereotyped pattern of expression. ORNs exhibited GLUT1 labeling in soma, dendrites, and axon. SCs displayed GLUT1 labeling throughout their cell length, whereas MCT1 and GLUT3 localize to their apical portion, possibly including the microvilli. Additionally, GLUT1 and MCT1 were detected in endothelial cells and GLUT1, GLUT3, and MCT2 in the cells of the Bowman's gland. Our observations suggest an energetic coupling between SCs and Bowman's gland cells, where glucose crossing the blood-mucosa barrier through GLUT1 is incorporated by these epithelial cells. Once in the SCs, glucose can be metabolized to lactate, which could be transported by MCTs into the Bowman's gland duct, where it can be used as metabolic fuel. Furthermore, SCs may export glucose and lactate to the mucous layer, where they may serve as possible energy supply to the cilia.

The Basal Forebrain Modulates Neuronal Response in an Active Olfactory Discrimination Task.

Successful completion of sensory decision-making requires focusing on relevant stimuli, adequate signal/noise ratio for stimulus discrimination, and stimulus valence evaluation. Different brain regions are postulated to play a role in these computations; however, evidence suggests that sensory and decision-making circuits are required to interact through a common neuronal pathway to elicit a context-adequate behavioral response. Recently, the basal forebrain (BF) region has emerged as a good candidate, since its heterogeneous projecting neurons innervate most of the cortical mantle and sensory processing circuits modulating different aspects of the sensory decision-making process. Moreover, evidence indicates that the BF plays an important role in attention and in fast modulation of neuronal activity that enhance visual and olfactory sensory perception. Here, we study in awake mice the involvement of BF in initiation and completion of trials in a reward-driven olfactory detection task. Using tetrode recordings, we find that BF neurons (including cholinergics) are recruited during sensory discrimination, reward, and interestingly slightly before trial initiation in successful discrimination trials. The precue neuronal activity was correlated with animal performance, indicating that this circuit could play an important role in adaptive context-dependent behavioral responses.

Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models.

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sensory information processing frequently leading to hypersensitivity across sensory modalities and consequently a wide array of behavioral symptoms. Insects and mammals engage primarily their sense of smell to create proper representations of the external world and guide adequate decision-making processes. This feature in combination with the exquisitely organized neuronal circuits found throughout the olfactory system (OS) and the wide expression of FMRP in brain regions that process olfactory information makes it an ideal model to study sensory alterations in FXS models. In the last decade several groups have taken advantage of these features and have used the OS of fruit fly and rodents to understand neuronal alteration giving rise to sensory perception issues. In this review article, we will discuss molecular, morphological and physiological aspects of the olfactory information processing in FXS models. We will highlight the decreased inhibitory/excitatory synaptic balance and the diminished synaptic plasticity found in this system resulting in behavioral alteration of individuals in the presence of odorant stimuli.

Mice Lacking M1 and M3 Muscarinic Acetylcholine Receptors Have Impaired Odor Discrimination and Learning.

The cholinergic system has extensive projections to the olfactory bulb (OB) where it produces a state-dependent regulation of sensory gating. Previous work has shown a prominent role of muscarinic acetylcholine (ACh) receptors (mAChRs) in regulating the excitability of OB neurons, in particular the M1 receptor. Here, we examined the contribution of M1 and M3 mAChR subtypes to olfactory processing using mice with a genetic deletion of these receptors, the M1-/- and the M1/M3-/- knockout (KO) mice. Genetic ablation of the M1 and M3 mAChRs resulted in a significant deficit in odor discrimination of closely related molecules, including stereoisomers. However, the discrimination of dissimilar molecules, social odors (e.g., urine) and novel object recognition was not affected. In addition the KO mice showed impaired learning in an associative odor-learning task, learning to discriminate odors at a slower rate, indicating that both short and long-term memory is disrupted by mAChR dysfunction. Interestingly, the KO mice exhibited decreased olfactory neurogenesis at younger ages, a deficit that was not maintained in older animals. In older animals, the olfactory deficit could be restored by increasing the number of new born neurons integrated into the OB after exposing them to an olfactory enriched environment, suggesting that muscarinic modulation and adult neurogenesis could be two different mechanism used by the olfactory system to improve olfactory processing.

Chile's dilemma: how to reinsert scientists trained abroad.

Chile is recognized worldwide as an emergent economy, with a great power in natural resource exploitation. Nonetheless, despite being one of the most developed countries in Latin America, Chile imports most of the knowledge and technology necessary to drive innovation in the country. The tight budget that the Chilean government assigned to research and development and the absence of a long-term scientific agenda contributed to a limited supply of scientists over the years. In an effort to reverse this scenario, Chile has created several fellowships, such as the Becas Chile Program (BCP) to encourage new generations to pursue graduate studies to ultimately advance research and development in situ. More than 6000 fellows are now being trained abroad, accumulating an incredible potential to transform the Chilean scientific environment as we know it.  Chile now faces a greater challenge: it has to offer infrastructure and job openings to the highly skilled professionals in whom it invested. Unfortunately no clear public policies to address this situation have been developed, partially due to the lack of a dedicated institution, such as a Ministry for Science and Technology which could focalize the necessary efforts to promote such policies. Therefore, in the meantime, Chilean scientist have been motivated to create different organizations, such as, Mas Ciencia para Chile and Nexos Chile-USA, to promote constructive discussion of the policies that could be implemented to improve the Chilean scientific situation. We hope that these and other organizations have a real impact on the generation of scientific guidelines that will finally contribute to the development of the country.

Coding odor identity and odor value in awake rodents.

In the last decade, drastic changes in the understanding of the role of the olfactory bulb and piriform cortex in odor detection have taken place through awake behaving recording in rodents. It is clear that odor responses in mitral and granule cells are strikingly different in the olfactory bulb of anesthetized versus awake animals. In addition, sniff recording has evidenced that mitral cell responses to odors during the sniff can convey information on the odor identity and sniff phase. Moreover, we review studies that show that the mitral cell conveys information on not only odor identity but also whether the odor is rewarded or not (odor value). Finally, we discuss how the substantial increase in awake behaving recording raises questions for future studies.