The posterior intralaminar thalamic nucleus promotes nose-to-nose contacts leading to prosocial reception in the sequence of mouse social interaction.

Efficient social interaction is essential for an adaptive life and consists of sequential processes of multisensory events with social counterparts. Social touch/contact is a unique component that promotes a sequence of social behaviours initiated by detection and approach to assess a social stimulus and subsequent touch/contact interaction to form prosocial relationships. We hypothesized that the thalamic sensory relay circuit from the posterior intralaminar nucleus of the thalamus (pIL) to the paraventricular nucleus of the hypothalamus (PVN) and the medial amygdala (MeA) plays a key role in the social contact-mediated sequence of events. We found that neurons in the pIL along with the PVN and MeA were activated by social encounters and that pIL activity was more abundant in a direct physical encounter, whereas MeA activity was dominant in an indirect through grid encounter. Chemogenetic inhibition of pIL neurons selectively decreased the investigatory approach and sniffing of a same-sex, but not an opposite-sex, stimulus mouse in an indirect encounter situation and decreased the facial/snout contact ratio in a direct encounter setting. Furthermore, chemogenetic pIL inhibition had no impact on anxiety-like behaviours or body coordinative motor behaviours, but it impaired whisker-related and plantar touch tactile sense. We propose that the pIL circuit can relay social tactile sensations and mediate the sequence of nonsexual prosocial interactions through an investigatory approach to tactile contact and thus plays a significant role in establishing prosocial relationships in mouse models.

Evaluation of radiation protection effectivity in a cardiac angiography room using visualized scattered radiation distribution.

In this study, we devised a radiation protection tool specifically designed for healthcare professionals and students engaged in cardiac catheterization to easily monitor and evaluate scattered radiation distribution across diverse C-arm angles and arbitrary physician associated staff positions-scrub nurse and technologist positions. In this study, scattered radiation distributions in an angiography room were calculated using the Monte Carlo simulation of particle and heavy ion transport code system (PHITS) code. Four visualizations were performed under different C-arm angles with and without radiation protection: (1) a dose profile, (2) a 2D cross-section, (3) a 3D scattered radiation distribution, and (4) a 4D scattered radiation distribution. The simulation results detailing the scattered radiation distribution in PHITS were exported in Visualization Toolkit format and visualized through the open-source visualization application ParaView for analysis. Visualization of the scattered dose showed that dose distribution depends on the C-arm angle and the x-ray machine output parameters (kV, mAs s-1, beam filtration) which depend upon beam angulation to the patient body. When irradiating in the posterior-anterior direction, the protective curtain decreased the dose by 62% at a point 80 cm from the floor, where the physician's gonads are positioned. Placing the protection board close to the x-ray tube reduced the dose by 24% at a location 160 cm from the floor, where the lens of the eye is situated. Notably, positioning the protection board adjacent to the physician resulted in a 95.4% reduction in incident air kerma. These visualization displays can be combined to understand the spread and direction of the scattered radiation distribution and to determine where and how to operate and place radiation protection devices, accounting for the different beam angulations encountered in interventional cases. This study showed that scatter visualization could be a radiation protection teaching aid for students and medical staff in angiography rooms.

Contrasting central and systemic effects of arginine-vasopressin on urinary marking behavior as a social signal in male mice.

Arginine-vasopressin (AVP) is a neurohypophyseal peptide that plays a critical role in the regulation of social behavior in mammals. Neuronal AVP regulates male-specific social signaling processes, such as exocrine urinary scent deposition and marking behavior in mice. In the periphery, AVP is transported to the portal bloodstream and acts as an antidiuretic hormone. These AVP dynamics imply that the central role of AVP in the stimulation of urinary marking is dissociated with the peripheral role of AVP in the retention of osmotic conditions. Using male BALB/c mice as subjects, peripheral injection of AVP decreased urinary marking and urination. In contrast, a central infusion of AVP facilitated urinary marking with no effect on urination, while an antagonist of the AVP 1a receptor inhibited marking. Centrally AVP-injected mice also exhibited typical behaviors, such as hiccough/sneeze-like reactions and flash scratching, particularly when confronted with a stimulus mouse through a wire mesh screen. Significant expression of these typical reactions in these mice resulted in the disruption of marking deposition. Further analysis of AVP synthesis illustrated that AVP levels increased in the midbrain but not in the circulation immediately after the test, particularly when confronted with a stimulus mouse. The central AVP regulates urinary marking and other typical behaviors in a dose- and situation-dependent manner. The sequential process implies that centrally synthesized AVP may be secreted into the circulation following immediate neuronal processes, and then peripheral AVP acts as an antidiuretic hormone on urinary marking behavior.

Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

Appropriate activation of the Ras/extracellular signal-regulated kinase (ERK) protein signaling cascade within the brain is crucial for optimal learning and memory. One key regulator of this cascade is the Nf1 Ras GTPase activating protein (RasGAP), which attenuates Ras/ERK signaling by converting active Ras is bound to guanosine triphosphate, activating Ras into inactive Ras is bound to guanosine diphosphate, inactivating Ras. A previous study using embryonic stem cells and embryonic stem cell-derived neurons indicated that Nf1 RasGAP activity is modulated by the highly regulated alternative splicing of Nf1 exon 23a. In this study, we generated Nf123aIN/23aIN mice, in which the splicing signals surrounding Nf1 exon 23a were manipulated to increase exon inclusion. Nf123aIN/23aIN mice are viable and exon 23a inclusion approaches 100% in all tissues, including the brain, where the exon is normally almost completely skipped. Ras activation and phosphorylation of ERK1/2 downstream of Ras are both greatly increased in Nf123aIN/23aIN mouse brain lysates, confirming that exon 23a inclusion inhibits Nf1 RasGAP activity in vivo as it does in cultured cells. Consistent with the finding of altered Ras/ERK signaling in the brain, Nf123aIN/23aIN mice showed specific deficits in learning and memory compared with Nf1+/+ mice. Nf123aIN/23aIN mice performed poorly on the T-maze and Morris water maze tests, which measure short- and long-term spatial memory, respectively. In addition, Nf123aIN/23aIN mice showed abnormally elevated context-dependent fear and a diminished ability to extinguish a cued fear response, indicating defective associative fear learning. Therefore, the regulated alternative splicing of Nf1 is an important mechanism for fine-tuning Ras/ERK signaling as well as learning and memory in mice.

Behavioral Consequences of a Bifacial Map in the Mouse Somatosensory Cortex.

The whisker system is an important sensory organ with extensive neural representations in the brain of the mouse. Patterned neural modules (barrelettes) in the ipsilateral principal sensory nucleus of the trigeminal nerve (PrV) correspond to the whiskers. Axons of the PrV barrelette neurons cross the midline and confer the whisker-related patterning to the contralateral ventroposteromedial nucleus of the thalamus, and subsequently to the cortex. In this way, specific neural modules called barreloids and barrels in the contralateral thalamus and cortex represent each whisker. Partial midline crossing of the PrV axons, in a conditional Robo3 mutant (Robo3R3-5cKO) mouse line, leads to the formation of bilateral whisker maps in the ventroposteromedial, as well as the barrel cortex. We used voltage-sensitive dye optical imaging and somatosensory and motor behavioral tests to characterize the consequences of bifacial maps in the thalamocortical system. Voltage-sensitive dye optical imaging verified functional, bilateral whisker representation in the barrel cortex and activation of distinct cortical loci following ipsilateral and contralateral stimulation of the specific whiskers. The mutant animals were comparable with the control animals in sensorimotor tests. However, they showed noticeable deficits in all of the whisker-dependent or -related tests, including Y-maze exploration, horizontal surface approach, bridge crossing, gap crossing, texture discrimination, floating in water, and whisking laterality. Our results indicate that bifacial maps along the thalamocortical system do not offer a functional advantage. Instead, they lead to impairments, possibly due to the smaller size of the whisker-related modules and interference between the ipsilateral and contralateral whisker representations in the same thalamus and cortex.SIGNIFICANCE STATEMENT The whisker sensory system plays a quintessentially important role in exploratory behavior of mice and other nocturnal rodents. Here, we studied a novel mutant mouse line, in which the projections from the brainstem to the thalamus are disrupted. This led to formation of bilateral whisker maps in both the thalamus and the cortex. The two whisker maps crowd in a space normally devoted to the contralateral map alone and in a nonoverlapping fashion. Stimulation of the whiskers on either side activates the corresponding region of the map. Mice with bilateral whisker maps perform well in general sensorimotor tasks but show poor performance in specific tests that require whisker-dependent tactile discrimination. These observations indicate that contralateral, instead of bilateral, representation of the sensory space plays a critical role in acuity and fine discrimination during somesthesis.

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization.

Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43M337V mice. Thus, this study suggests hemizygous TDP-43M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

Thalamic NMDA receptor function is necessary for patterning of the thalamocortical somatosensory map and for sensorimotor behaviors.

NMDARs play a major role in patterning of topographic sensory maps in the brain. Genetic knock-out of the essential subunit of NMDARs in excitatory cortical neurons prevents whisker-specific neural pattern formation in the barrel cortex. To determine the role of NMDARs en route to the cortex, we generated sensory thalamus-specific NR1 (Grin1)-null mice (ThNR1KO). A multipronged approach, using histology, electrophysiology, optical imaging, and behavioral testing revealed that, in these mice, whisker patterns develop in the trigeminal brainstem but do not develop in the somatosensory thalamus. Subsequently, there is no barrel formation in the neocortex yet a partial afferent patterning develops. Whisker stimulation evokes weak cortical activity and presynaptic neurotransmitter release probability is also affected. We found several behavioral deficits in tasks, ranging from sensorimotor to social and cognitive. Collectively, these results show that thalamic NMDARs play a critical role in the patterning of the somatosensory thalamic and cortical maps and their impairment may lead to pronounced behavioral defects.

Effects of the estrous cycle and ovarian hormones on central expression of interleukin-1 evoked by stress in female rats.

Exposure to stressors such as foot shock (FS) leads to increased expression of multiple inflammatory factors, including the proinflammatory cytokine interleukin-1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuations in gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of 17-ß-estradiol (E2) and progesterone (Pg) in regulating the cytokine response within the paraventricular nucleus (PVN) of the hypothalamus through analysis of gene expression with real-time RT-PCR. Regularly cycling female rats showed a stress-induced increase in PVN IL-1 levels during the diestrous, proestrous, and estrous stages. During the metestrous stage, no change in IL-1 levels was seen following FS; however, estrogen receptor (ER)-ß levels did increase. Ovariectomy resulted in an increase in PVN IL-1 levels, which was attenuated by treatment with estradiol benzoate (10 or 50 µg), indicating an E2-mediated anti-inflammatory effect. Ovariectomized rats treated with Pg (500 or 1,250 µg) showed no alteration in IL-1 levels, but Pg did up-regulate ER-ß gene expression. The results from the current study implicate a potential mechanism through which high availability of endogenous Pg during the metestrous stage increases ER-ß sensitivity, which in turn attenuates the PVN IL-1 response to stress. Thus, the interaction between gonadal steroid hormones and their central receptors may exert a powerful inhibitory effect on neuroimmune consequences of stress throughout the estrous cycle.

Directional vector visualization of scattered rays in mobile c-arm fluoroscopy.

Previous radiation protection-measure studies for medical staff who perform X-ray fluoroscopy have employed simulations to investigate the use of protective plates and their shielding effectiveness. Incorporating directional information enables users to gain a clearer understanding of how to position protective plates effectively. Therefore, in this study, we propose the visualization of the directional vectors of scattered rays. X-ray fluoroscopy was performed; the particle and heavy-ion transport code system was used in Monte Carlo simulations to reproduce the behavior of scattered rays in an X-ray room by reproducing a C-arm X-ray fluoroscopy system. Using the calculated results of the scattered-ray behavior, the vectors of photons scattered from the phantom were visualized in three dimensions. A model of the physician was placed on the directional vectors and dose distribution maps to confirm the direction of the scattered rays toward the physician when the protective plate was in place. Simulation accuracy was confirmed by measuring the ambient dose equivalent and comparing the measured and calculated values (agreed within 10%). The directional vectors of the scattered rays radiated outward from the phantom, confirming a large amount of backscatter radiation. The use of a protective plate between the patient and the physician's head part increased the shielding effect, thereby enhancing radiation protection for the physicians compared to cases without the protective plate. The use of directional vectors and the surrounding dose-equivalent distribution of this method can elucidate the appropriate use of radiation protection plates.

[Evaluation of Transmitted X-ray Spectrum, Lead Equivalent, and Uniformity of Radiation Protective Clothing Made of Lead-containing and Lead-free Materials].

PURPOSE: The purpose of this study was to evaluate the protective performance of several new radiation-protective clothing and to clarify issues of quality control. METHODS: The composition of the shielding elements was analyzed using X-ray fluorescence analysis, and the energy spectrum of transmitted X-rays was measured. Furthermore, the lead equivalent and uniformity were measured from the transmitted X-ray doses according to Japanese industrial standards (JIS). Uniformity was evaluated by transmitting X-ray images of each radiation protective clothing in addition to the conventional method. RESULTS: The energy spectrum showed K-absorption edges of lead, bismuth, tin, etc., which were detected in the composition analysis. The multi-layered protective material maintained higher shielding ability at high tube voltages. In addition, X-ray images of the radiation-protective clothing showed uneven density and dots, and the differences in uniformity measurement methods and points that didn't meet the required shielding capacity were seen. CONCLUSION: The current JIS does not allow accurate evaluation of the lead equivalent and uniformity, so visual evaluation of X-ray images is important. It is necessary to establish standardized standards for quality control performed by each facility.

Developing simulation-based learning application for radiation therapy students at pre-clinical stage.

INTRODUCTION: Simulation-based education has been particularly valuable as a preclinical training method that adequately prepares students for clinical practice, including simulation in educational programs enhances the quality of learning outcomes. However, relevant previous research has exhibited several crucial limitations, with most of them having focused solely on the setup procedures. This study aimed to outline the development of an educational application in radiationtherapy and emphasizes the essential factors that radiation therapist technologists(RTTs) must consider in the treatment room from the perspective of experienced RTTs. METHOD: We connected the virtual pendants to the linear accelerator components using C# programming and Unity. Customized scripts were assigned to specific linear accelerator (LINAC) functions, and the patient and RTT avatars were developed. We also included audio feedback for the realistic gantry movement sounds. RESULT: This study outlines various aspects of radiotherapy procedures duringtreatment, such as the simulation of patient positioning, treatment fields, and pendantfunctions, aimed toward enabling the effective use of virtual reality technology inradiation therapy. DISCUSSION: This study explores the potential of an avatar-based app for radiotherapy education, providing foundational data for future trials. CONCLUSION: Simulation learning is the most advantageous pre-clinical instrument for equipping students with the skills necessary for clinical practice. This study's resultsare expected to facilitate radiotherapy students' adoption of clinical replacement applications and improve collaborative partnerships and knowledge sharing. Notably, this application complements traditional learning methods, further enhancing the overall educational experience.

Optimum delineation of skin structure for dose calculation with the linear Boltzmann transport equation algorithm in radiotherapy treatment planning.

This study investigated the effectiveness of placing skin-ring structures to enhance the precision of skin dose calculations in patients who had undergone head and neck volumetric modulated arc therapy using the Acuros XB algorithm. The skin-ring structures in question were positioned 2 mm below the skin surface (skin A) and 1 mm above and below the skin surface (skin B) within the treatment-planning system. These structures were then tested on both acrylic cylindrical and anthropomorphic phantoms and compared with the Gafchromic EBT3 film (EBT3). The results revealed that the maximum dose differences between skins A and B for the cylindrical and anthropomorphic phantoms were approximately 12% and 2%, respectively. In patients 1 and 2, the dose differences between skins A and B were 9.2% and 8.2%, respectively. Ultimately, demonstrated that the skin-dose calculation accuracy of skin B was within 2% and did not impact the deep organs.

The Usefulness of a Virtual Environment-Based Patient Setup Training System for Radiation Therapy.

In radiation therapy, patient setup is important for improving treatment accuracy. The six-axis couch semi-automatically adjusts the patient's position; however, adjusting the patient to twist is difficult. In this study, we developed and evaluated a virtual reality setup training tool for medical students to understand and improve their patient setup skills for radiation therapy. First, we set up a simulated patient in a virtual space to reproduce the radiation treatment room. A gyro sensor was attached to the patient phantom in real space, and the twist of the phantom was linked to the patient in the virtual space. Training was conducted for 24 students, and their operation records were analyzed and evaluated. The training's efficacy was also evaluated through questionnaires provided at the end of the training. The total time required for patient setup tests before and after training decreased significantly from 331.9 s to 146.2 s. As a result of the questionnaire regarding the usability of training to the trainee, most were highly evaluated. We found that training significantly improved students' understanding of the patient setup. With the proposed system, trainees can experience a simulated setup that can aid in deepening their understanding of radiation therapy treatments.

Simulating the head of a TrueBeam linear particle accelerator and calculating the photoneutron spectrum on the central axis of a 10-MV photon using particle and heavy-ion transport system code.

Photon energy is higher than the (γ,n) threshold, allowing it to interact with the nuclei of materials with high z properties and liberate fast neutrons. This represents a potentially harmful source of radiation for humans and the environment. This study validated the Monte Carlo simulation, using the particle and heavy-ion transport code system (PHITS) on a TrueBeam 10-MV linear particle accelerator's head shielding model and then used this PHITS code to simulate a photo-neutron spectrum for the transport of the beam. The results showed that, when comparing the simulated to measured PDD and crosslines, 100% of the γ-indexes were <1 (γ3%/3mm) for both simulations, for both phase-space data source and a mono energy source. Neutron spectra were recorded in all parts of the TrueBeam's head, as well as photon neutron spectra at three points on the beamline.

Adolescent social isolation disrupts developmental tuning of neuropeptide circuits in the hypothalamus to amygdala regulating social and defensive behavior.

Engaging in positive social (i.e., prosocial) interactions during adolescence acts to modulate neural circuits that determine adult adaptive behavior. While accumulating evidence indicates that a strong craving for prosocial behavior contributes to sustaining neural development, the consequences of social deprivation during adolescence on social neural circuits, including those involving oxytocin (OXT) and vasopressin (AVP), are poorly characterized. We evaluated adaptive behaviors in socially isolated mice, including anxiety-like, social, and defensive behaviors, along with OXT and AVP neural profiles in relevant brain regions. Social isolation from postnatal day (P-)22 to P-48 induced enhanced defensive and exploratory behaviors, in nonsocial and social contexts. Unlike OXT neurons, AVP+ cell density in the paraventricular nucleus of the hypothalamus increases with age in males. Social isolation also modulated gene expression in the medial amygdala (MeA), including the upregulation of OXT receptors in males and the downregulation of AVP1a receptors in both sexes. Socially isolated mice showed an enhanced defensive, anogenital approach toward a novel adult female during direct social interactions. Subsequent c-Fos mapping revealed diminished neural activity in restricted brain areas, including the MeA, lateral septum, and posterior intralaminar nucleus of the thalamus, in socially isolated mice. These data indicate that neural signals arising from daily social interactions invoke region-specific modification of neuropeptide expression that coordinates with altered defensiveness and neural responsivities, including OXT- and AVP-projecting regions. The present findings indicate an involvement of OXT and AVP circuits in adolescent neural and behavioral plasticity that is tuned by daily social interaction.

The receptor guanylyl cyclase type D (GC-D) ligand uroguanylin promotes the acquisition of food preferences in mice.

Rodents rely on olfactory stimuli to communicate information between conspecifics that is critical for health and survival. For example, rodents that detect a food odor simultaneously with the social odor carbon disulfide (CS(2)) will acquire a preference for that food. Disruption of the chemosensory transduction cascade in CS(2-)sensitive olfactory sensory neurons (OSNs) that express the receptor guanylyl cyclase type D (GC-D; GC-D+ OSNs) will prevent mice from acquiring these preferences. GC-D+ OSNs also respond to the natriuretic peptide uroguanylin, which is excreted into urine and feces. We analyzed if uroguanylin could also act as a social stimulus to promote the acquisition of food preferences. We found that feces of mice that had eaten odored food, but not unodored food, promoted a strong preference for that food in mice exposed to the feces. Olfactory exploration of uroguanylin presented with a food odor similarly produced a preference that was absent when mice were exposed to the food odor alone. Finally, the acquisition of this preference was dependent on GC-D+ OSNs, as mice lacking GC-D (Gucy2d(-)(/-) mice) showed no preference for the demonstrated food. Together with our previous findings, these results demonstrate that the diverse activators of GC-D+ OSNs elicit a common behavioral result and suggest that this specialized olfactory subsystem acts as a labeled line for a type of associative olfactory learning.

Revisiting sociability: Factors facilitating approach and avoidance during the three-chamber test.

The three-chamber test, the so-called sociability test, has been widely used to assess social deficits based on impaired socially oriented investigations in rodent models. An innate motivation for investigating conspecifics is theoretically a prerequisite for gaining sociability scores in this paradigm. However, several relevant factors mediating investigatory motives, such as familiarity, attractiveness, and aggression, may affect sociability scores, which must be verified to obtain an adequate evaluation of the psychiatric phenotypes exhibited by disease-relevant rodent models. We assessed the social and non-social factors that mediate proximity preference by the three-chamber test with standard C57BL/6 J (B6) mice and low sociability BTBR+ltpr3tf/J (BTBR) mice. Strains of the opponents had no effect. Sexual cues (i.e., opposite sex) increased proximity preference in both strains of mice; in contrast, novel objects induced an approach in B6 mice but avoidance in BTBR mice. Single-housing before testing, stimulated social motive, affected BTBR mice but not B6 mice. BTBR females showed increased proximity preference across the sessions, and BTBR males showed increased preference toward a male B6 stimulus, but not a male BTBR stimulus. The male preference was restored when the male BTBR stimulus was anesthetized. In addition, self-grooming was facilitated by social and non-social novelty cues in both strains. B6 mice predominantly exhibited an investigatory approach toward social or non-social stimuli, whereas BTBR mice recognized social cues but tended to show avoidance. The three-chamber test could evaluate approach-avoidance strategies in target mouse strains that comprise innate social distance between mice.

Serotonergic mediation of the brain-wide neurogenesis: Region-dependent and receptor-type specific roles on neurogenic cellular transformation.

Brain serotonin (5-hydroxytryptamine, 5-HT) is a key molecule for the mediation of depression-related brain states, but the neural mechanisms underlying 5-HT mediation need further investigation. A possible mechanism of the therapeutic antidepressant effects is neurogenic cell production, as stimulated by 5-HT signaling. Neurogenesis, the proliferation of neural stem cells (NSCs), and cell differentiation and maturation occur across brain regions, particularly the hippocampal dentate gyrus and the subventricular zone, throughout one's lifespan. 5-HT plays a major role in the mediation of neurogenic processes, which in turn leads to the therapeutic effect on depression-related states. In this review article, we aim to identify how the neuronal 5-HT system mediates the process of neurogenesis, including cell proliferation, cell-type differentiation and maturation. First, we will provide an overview of the neurogenic cell transformation that occurs in brain regions containing or lacking NSCs. Second, we will review brain region-specific mechanisms of 5-HT-mediated neurogenesis by comparing regions localized to NSCs, i.e., the hippocampus and subventricular zone, with those not containing NSCs. Highlighting these 5-HT mechanisms that mediate neurogenic cell production processes in a brain-region-specific manner would provide unique insights into the role of 5-HT in neurogenesis and its associated effects on depression.

Oxytocin neurons in the paraventricular nucleus of the hypothalamus circuit-dependently regulates social behavior, which malfunctions in BTBR mouse model of autism.

Oxytocin (OXT) a neuropeptide synthesized in the hypothalamic nuclei has a variety of function including socio-emotional processes in mammals. While the neural circuits and signaling pathways in central OXT converge in the paraventricular nucleus of the hypothalamus (PVN), we illuminate specific function of discrete PVN OXT circuits, which connect to the medial amygdala (MeA) and the bed nucleus of the stria terminalis (BnST) in mouse models. The OXTPVN→BnST projections are innervated from entire portions of the PVN, while those OXTPVN→MeA projections are asymmetrically innervated from the posterior portion of the PVN. Compared with OXT neurons in B6 wild type mice, BTBR mice that are recognized as a behavior-based autism model exhibited defect in the OXTPVN→BnST projection. We demonstrate that chemogenetic activation of OXTPVN→MeA circuit enhances anxiety-like behavior and facilitates social approach behavior, while activation of OXTPVN→BnST circuit suppresses anxiety-like behavior along with inhibiting social approach. This chemogenetic manipulation on the OXTPVN→BnST circuit proves ineffective in BTBR mice. Accordingly, chemogenetic activation of OXTPVN neurons that stimulate both OXT circuits induces OXT receptor expressions in both MeA and BnST as with those by social encounter in B6 mice. The induction of OXT receptor genes in the BnST was not observed in BTBR mice. These data support the hypothesis that OXT circuits serve as a regulator for OXT signaling in PVN to control socio-emotional approach/avoidance behavior, and a defect of OXTPVN→BnST circuit contributes to autism-like social phenotypes in BTBR mice.

Serotonergic circuit dysregulation underlying autism-related phenotypes in BTBR mouse model of autism.

The inbred mouse strain, BTBR T+Itpr3tf/J (BTBR), possesses neuronal and circuit abnormalities that underlie atypical behavioral profiles resembling the major symptoms of human autism spectrum disorder (ASD). Forebrain serotonin (5-HT) transmission has been implicated in ASD-related behavioral alterations. In this study, we assessed 5-HT signals and the functional responsiveness in BTBR mice compared to standard C57BL/6J (B6) control mice to elucidate how 5-HT alterations contribute to behavioral abnormalities in BTBR mice. A lower number of 5-HT neurons in the median raphe, but not in the dorsal raphe, was observed in male and female BTBR mice. Acute systemic injection of buspirone, a 5-HT1A receptor agonist, induced c-Fos in several brain regions in both B6 and BTBR mice; however, blunted c-Fos induction in BTBR mice was documented in the cingulate cortex, basolateral amygdala (BLA), and ventral hippocampus (Hipp). Decreased c-Fos responses in these regions are associated with a lack of buspirone effects on anxiety-like behavior in BTBR mice. Analysis of mRNA expression following acute buspirone injection indicated that 5HTR1a gene downregulation (or upregulation) occurred in the BLA and Hipp of B6 mice, respectively, but not BTBR mice. The mRNA expression of factors associated with neurogenesis or the pro-inflammatory state was not consistently altered by acute buspirone injection. Therefore, 5-HT responsivity via 5-HT1A receptors in the BLA and Hipp are linked to anxiety-like behavior, in which circuits are disrupted in BTBR mice. Other distinct 5-HT circuits from the BLA and Hipp that regulate social behavior are restricted but preserved in BTBR mice.