Medial Nucleus Research Articles

Impact of social stress in early ontogenesis on food addiction and ghrelin levels in the hypothalamus of rats

BACKGROUND: Factors that can trigger episodes of binge (compulsive) eating include psychological and physical stress. Our studies have shown that maternal deprivation in early ontogenesis leads to an increase in elements of gambling addiction in the Iowa Gambling Task test. This raises the question of the role of maternal deprivation in the development of other types of non-chemical addictions, particularly food addiction. AIM: To study the role of ghrelin in the manifestation of food addiction elements in rats subjected to maternal deprivation in early ontogenesis. MATERIALS AND METHODS: Wistar rats were separated from their mothers for 180 minutes daily from day 2 to day 12 after birth. Male rats aged 90–100 days were used in the experiments. To induce compulsive overeating, the animals were given a high-carbohydrate diet (a mixture based on chocolate paste) for 1 hour every third day for 1.5 months. Fifteen minutes before feeding, the chocolate paste was placed within 5 cm of the rat’s reach with visual contact. After compulsive overeating was established, the number and area of ghrelin-producing neuroendocrine cells in the hypothalamus were analyzed using immunohistochemistry in intact rats and animals subjected to maternal deprivation stress. RESULTS: It was shown that intermittent consumption of the chocolate mixture predicted overeating in rats, independent of weight gain or obesity, as a result of compulsive overeating. In studying the effect of maternal deprivation on chocolate consumption, it was found that the average daily consumption in the maternal deprivation group increased (p 0.001) compared to the control group. However, there was no significant difference in standard food consumption between the maternal deprivation and control groups. The number and area of ghrelin-producing neuroendocrine cells in the lateral portion of the medial arcuate nucleus of the hypothalamus were reduced in rats after maternal deprivation. CONCLUSIONS: It was concluded that early psychogenic stress from maternal deprivation causes a dysregulation of the ghrelin system, contributing to elements of food addiction in rats.

Functional localization of the human auditory and visual thalamus using a thalamic localizer functional magnetic resonance imaging task

Abstract Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due, in part, to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmarked their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.

Unique cortical and subcortical activation patterns for different conspecific calls in marmosets

The common marmoset (Callithrix jacchus) is known for its highly vocal nature, displaying a diverse range of calls. Functional imaging in marmosets has shown that the processing of conspecific calls activates a brain network that includes fronto-temporal areas. It is currently unknown whether different call types activate the same or different networks. In this study, nine adult marmosets (four females) were exposed to four common vocalizations (phee, chatter, trill, and twitter), and their brain responses were recorded using event-related fMRI at 9.4T. We found robust activations in the auditory cortices, encompassing core, belt, and parabelt regions, and in subcortical areas like the inferior colliculus, medial geniculate nucleus, and amygdala in response to these calls. Although a common network was engaged, distinct activity patterns were evident for different vocalizations that could be distinguished by a 3D convolution neural network, indicating unique neural processing for each vocalization. Our findings also indicate the involvement of the cerebellum and medial prefrontal cortex (mPFC) in distinguishing particular vocalizations from others.Significance StatementThis study investigates the neural processing of vocal communications in the common marmoset (Callithrix jacchus). Utilizing event-related fMRI at 9.4T, we demonstrate that different calls (phee, chatter, trill, and twitter) elicit distinct brain activation patterns, challenging the notion of a uniform neural network for all vocalizations. Each call type distinctly engages various regions within the auditory cortices and subcortical areas. These findings offer insights into the evolutionary mechanisms of primate vocal perception and provide a foundation for understanding the origins of human speech and language processing.

Identifying the bioimaging features of Alzheimer’s disease based on pupillary light response-driven brain-wide fMRI in awake mice

Pupil dynamics has emerged as a critical non-invasive indicator of brain state changes. In particular, pupillary-light-responses (PLR) in Alzheimer’s disease (AD) patients show potential as biomarkers for brain degeneration. To investigate AD-specific PLR and its underlying neuromodulatory sources, we combine high-resolution awake mouse fMRI with real-time pupillometry to map brain-wide event-related correlation patterns based on illumination-driven pupil constriction (Pc\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${P}_{c}$$\\end{document}) and post-illumination pupil dilation recovery (amplitude, Pd\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${P}_{d}$$\\end{document}, and time, T). The Pc\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${P}_{c}$$\\end{document}-driven differential analysis reveals altered visual signal processing and reduced thalamocortical activation in AD mice in comparison with wild-type (WT) control mice. In contrast, the post-illumination pupil dilation recovery-based fMRI highlights multiple brain areas associated with AD brain degeneration, including the cingulate cortex, hippocampus, septal area of the basal forebrain, medial raphe nucleus, and pontine reticular nuclei (PRN). Additionally, the brain-wide functional connectivity analysis highlights the most significant changes in PRN of AD mice, which serves as the major subcortical relay nuclei underlying oculomotor function. This work integrates non-invasive pupil-fMRI measurements in preclinical models to identify pupillary biomarkers based on brain-wide functional changes, including neuromodulatory dysfunction coupled with AD brain degeneration.

Neural correlates of sensorimotor adaptation: thalamic contributions to learning from sensory prediction error

Understanding the neural mechanism of sensorimotor adaptation is essential to reveal how the brain learns from errors, a process driven by sensory prediction errors. While the previous literature has focused on cortical and cerebellar changes, the involvement of the thalamus has received less attention. This functional magnetic resonance imaging study aims to explore the neural substrates of learning from sensory prediction errors with an additional focus on the thalamus. Thirty participants adapted their goal-directed reaches to visual feedback rotations introduced in a step-wise manner, while reporting their predicted visual consequences of their movements intermittently. We found that adaptation initially engaged the cerebellum and fronto-parietal cortical regions, which persisted as adaptation progressed. By the end of adaptation, additional regions within the fronto-parietal cortex and medial pulvinar of the thalamus were recruited. Another finding was the involvement of bilateral medial dorsal nuclei, which showed a positive correlation with the level of motor adaptation. Notably, the gradual shift in the predicted hand movement consequences was associated with activity in the cerebellum, motor cortex and thalamus (ventral lateral, medial dorsal, and medial pulvinar). Our study presents clear evidence for an involvement of the thalamus, both classical ‘motor’ and higher-order nuclei, in error-based motor learning.

Effects of the two-pore potassium channel subunit Task5 on neuronal function and signal processing in the auditory brainstem

Processing of auditory signals critically depends on the neuron’s ability to fire brief, precisely timed action potentials (APs) at high frequencies and high fidelity for prolonged times. This requires the expression of specialized sets of ion channels to quickly repolarize neurons, prevent aberrant AP firing and tightly regulate neuronal excitability. Although critically important, the regulation of neuronal excitability has received little attention in the auditory system. Neuronal excitability is determined to a large extent by the resting membrane potential (RMP), which in turn depends on the kind and number of ion channels open at rest; mostly potassium channels. A large part of this resting potassium conductance is carried by two-pore potassium channels (K2P channels). Among the K2P channels, the subunit Task5 is expressed almost exclusively in the auditory brainstem, suggesting a specialized role in auditory processing. However, since it failed to form functional ion channels in heterologous expression systems, it was classified “non-functional” for a long time and its role in the auditory system remained elusive. Here, we generated Task5 knock-out (KO) mice. The loss of Task5 resulted in changes in neuronal excitability in bushy cells of the ventral cochlear nucleus (VCN) and principal neurons of the medial nucleus of the trapezoid body (MNTB). Moreover, auditory brainstem responses (ABRs) to loud sounds were altered in Tasko5-KO mice. Thus, our study provides evidence that Task5 is indeed a functional K2P subunit and contributes to sound processing in the auditory brainstem.

Dietary omega-3 polyunsaturated fatty acids reduce cytochrome c oxidase in brain white matter and sensorimotor regions while increasing functional interactions between neural systems related to escape behavior in postpartum rats

IntroductionPreviously, we showed that omega-3 polyunsaturated fatty acid n-3 (PUFA) supplementation improved the performance of postpartum rats in the shuttle box escape test (SBET).MethodsThe brains of these rats were used in the current study which examined brain cytochrome c oxidase (CCO) activity in white matter bundles and 39 regions spanning sensorimotor, limbic, and cognitive areas to determine the effects of n-3 PUFAs on neural metabolic capacity and network interactions.ResultsWe found that n-3 PUFA supplementation decreased CCO activity in white matter bundles, deep and superficial areas within the inferior colliculus, the anterior and barrel field regions of the primary somatic sensorimotor cortex, the secondary somatic sensorimotor cortex, the lateral, anterior regions of the secondary visual cortex and the ventral posterior nucleus of the thalamus, and the medial nucleus of the amygdala. Structural equation modeling revealed that animals consuming diets without n-3 PUFAs exhibited fewer inter-regional interactions when compared to those fed diets with n-3 PUFAs. Without n-3 PUFAs, inter-regional interactions were observed between the posterior cingulate cortex and amygdala as well as among amygdala subregions. With n-3 PUFAs, more inter-regional interactions were observed, particularly between regions associated with fear memory processing and escape. Correlations between regional CCO activity and SBET behavior were observed in rats lacking dietary n-3 PUFAs but not in those supplemented with these nutrients.DiscussionIn conclusion, consumption of n-3 PUFAs results in reduced CCO activity in white matter bundles and sensorimotor regions, reflecting more efficient neurotransmission, and an increase in inter-regional interactions, facilitating escape from footshock.

An Indirect Pathway from the Rat Interstitial Nucleus of Cajal to the Vestibulocerebellum Involved in Vertical Gaze Holding.

The neural network, including the interstitial nucleus of Cajal (INC), functions as an oculomotor neural integrator involved in the control of vertical gaze holding. Impairment of the vestibulocerebellum (VC), including the flocculus (FL), has been shown to affect vertical gaze holding, indicating that the INC cooperates with the VC in controlling this function. However, a network between the INC and VC has not been identified. In this study, we aimed to obtain anatomical evidence of a neural pathway from the INC to the VC (the INC-VC pathway) in rats. Injection of dextran-conjugated Alexa Fluor 488 or adeno-associated virus 2-retro (AAV2retro) expressing GFP into the FL or another VC region (uvula/nodulus) did not reveal any retrogradely labeled neurons in the INC, suggesting that INC neurons do not project directly to the VC. Rabies virus-based transsynaptic tracing experiments revealed that the INC-VC pathway is mediated via synaptic connections with the prepositus hypoglossi nucleus (PHN) and medial vestibular nucleus (MVN). The INC neurons in the INC-VC pathway were mainly localized bilaterally within the rostral region of the INC. Transsynaptic tracing experiments involving the INC-FL pathway revealed that INC neurons connected to the FL via the bilateral PHN and MVN. These results indicate that the INC-VC pathway is not a direct pathway but is mediated via the PHN and MVN. These findings can provide clues for understanding the network mechanisms responsible for vertical gaze holding.

Obliteration of a glycinergic projection to the medial geniculate in an animal model of autism.

Auditory dysfunction affects the vast majority of people with autism spectrum disorder (ASD) and can range from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid (VPA) is associated with significant risk of an ASD diagnosis in humans and timed in utero exposure to VPA is utilized as an animal model of ASD. VPA-exposed rats have significantly fewer neurons in their auditory brainstem, thalamus and cortex, reduced ascending projections to the midbrain and thalamus and reduced descending projections from the cortex to the auditory midbrain. Consistent with these anatomical changes, VPA-exposed animals also have abnormal auditory brainstem responses. We have recently described a significant ascending projection from calbindin-positive neurons in the medial nucleus of the trapezoid body (MNTB) to the ventral division of the medial geniculate (vMG) in rats that bypasses the central nucleus of the inferior colliculus (CNIC). Since we found that axonal projections to the vMG in VPA-exposed rats are reduced beyond what is predicted from neuron loss alone, we hypothesize that VPA exposure would result in a significant reduction in the MNTB projection to the vMG. We examined this hypothesis by quantifying the proportion of retrogradely-labeled neurons in the MNTB of control and VPA-exposed animals after injections of retrograde tracers in the CNIC and vMG in control and VPA-exposed animals. Our results indicate that in control animals, the MNTB forms the largest projection from the superior olivary complex to the MG and that this projection is nearly abolished by in utero VPA exposure.

Neuroscience of the Human Thalamus Related to Acute Pain and Chronic 'Thalamic' Pain.

The association of posterior thalamic strokes with the presence of chronic 'thalamic' pain, was described in the early 1900s and revisited in a recent review of these patients. Acute pain in corporal structures is associated with the spinothalamic tract (STT) which originates in the dorsal horn of the spinal cord, while that associated with cranial structures is associated with the spinal division of the trigeminal nucleus. These pathways terminate in the ventral posterior nucleus (VP) including its posterior and inferior subnuclei, and its core which is classically associated with tactile and haptic functions. In medial nuclei (medial dorsal and intralaminar) receptive fields are large and stimulation evokes diffuse unpleasant sensations and pain while neurons in these nuclei subserve cognitive processes of attention, alerting, and conditioning. In the lateral nuclei neurons have small receptive and projected fields and high resolution of responses to somatic stimuli. Neurons in the lateral nuclei respond to stimuli producing pain, temperature, and visceral sensations while stimulation evokes similar sensations. Small strokes in VP core versus structures located inferior and posterior are associated with 'thalamic' pain and decreased tactile, painful and cold sensations, and with decreased evoked potentials for painful (laser) heat and median nerve stimulation (electrical). Lesions of VP, but not Vmpo, are associated with 'thalamic' pain, contrary to the recent 'disinhibition' model. We review the evidence that the lateral nuclei are associated with multiple processes including tactile, nociceptive, visceral and thermal content of stimuli, while the medial nuclei are related to cognitions about those stimuli.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice.

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Commissural and monosynaptic inputs to medial vestibular nucleus GABAergic neurons in mice.

MVN GABAergic neurons is involved in the rebalance of commissural system contributing to alleviating acute peripheral vestibular dysfunction syndrome. This study aims to depict monosynaptic inputs to MVN GABAergic neurons. The modified rabies virus-based retrogradation method combined with the VGAT-IRES-Cre mice was used in this study. Moreover, the commissural connections with MVN GABAergic neurons were analyzed. We identified 60 nuclei projecting to MVN GABAergic neurons primarily distributed in the cerebellum and the medulla. The uvula-nodulus, gigantocellular reticular nucleus, prepositus nucleus, intermediate reticular nucleus, and three other nuclei sent dense inputs to MVN GABAergic neurons. The medial (fastigial) cerebellar nucleus, dorsal paragigantocellular nucleus, lateral paragigantocellular nucleus and 10 other nuclei sent moderate inputs to MVN GABAergic neurons. Sparse inputs to MVN GABAergic neurons originated from the nucleus of the solitary tract, lateral reticular nucleus, pedunculopontine tegmental nucleus and 37 other nuclei. The MVN GABAergic neurons were regulated by the contralateral MVN, lateral vestibular nucleus, superior vestibular nucleus, and inferior vestibular nucleus. Our study contributes to further understanding of the vestibular dysfunction in terms of neural circuits and search for new strategies to facilitate vestibular compensation.

8631 Tanycytic TSHR Activation Regulates Blood-Hypothalamus Barrier Plasticity, Ingestive Behavior, Adipose Remodeling, and Body Weight

Abstract Disclosure: L. Cullen: None. H.S. Kannangara: None. R. Witztum: None. J. Burgess: None. S. Miyashita: None. A. Gumerova: None. F. Korkmaz: None. S.L. Sims: None. U. Cheliadinova: None. G. Pevnev: None. O. Moldavski: None. O. Barak: None. S. Rojekar: None. V. Laurencin: None. T. Frolinger: None. T. Yuen: None. K. Goosens: None. W. Zhou: None. V. Ryu: None. M. Zaidi: None. The notion that TSH acts solely on its primary endocrine target, the thyroid gland, has long been challenged (Abe et al., 2003; PMID: 14567913). More recently, however, we and others have used single transcript technology to document, for the first time, Tshr expression in over 173 brain regions and nuclei, particularly hypothalamic tanycytes (eLife, 2022, PMID: 36052994). The latter cells are known to convey metabolic information across the blood-hypothalamus barrier (BHB) and regulate energy homeostasis. To study whether tanycytic TSHRs have a role in the regulation of BHB permeability, ingestive behavior, adipose tissue remodeling and body weight, we first compared BHB vascular permeability of food-deprived and ad libitum-fed Tshr+/- mice and their wild type (WT) littermates. Transmission electron microscopy and immunostaining was used to study the expression of the constitutive tight junction protein claudin-1 and the glycoprotein MECA-32, which are expressed in tanycytes and endothelial cells, respectively. In loss-of-function studies, fasting of Tshr+/- mice and of WT mice significantly increased the organization of tanycytic honeycomb pattern of claudin-1 and MECA-32-associated fenestral diaphragms in the median eminence and arcuate nucleus, suggesting decreased BHB permeability. As a result, peanut butter consumption following fasting was decreased significantly compared to control mice. In gain-of-function studies, intracerebroventricular (ICV) infusions of a highly specific TSHR agonist, MS438, profoundly increased BHB permeability in fasted mice, as evidenced by decreased claudin-1 and MECA-32 immunostaining and significant increases in peanut butter consumption. This was associated with greater loss of fat mass and body weight following food deprivation, as well as increased influx of fatty acids across the BHB, increased NPY expression (as a measure of increased appetite), and increased secretion of ghrelin from the stomach fundus. We further performed c-Fos immunostaining in brain centers regulating ingestive behavior. ICV MS438 significantly decreased c-Fos immunoreactivity in the hypothalamic paraventricular nucleus, arcuate nucleus and the nucleus of the solitary tract. Early studies using CRSIPR/Cas9 to delete Tshrs in tanycytes via ICV injection resulted in reduced body weight following food deprivation. Finally, using PRV152 (injected into fat tissue) and PRV614 (injected into stomach fundus), we colocalized immunostaining in the hypothalamic paraventricular nucleus, and hindbrain raphe pallidus. Collectively, these data establish a new role for tanycytic TSHRs in regulating BHB plasticity, ingestive behavior, adipose tissue remodeling, and body weight through a novel fast-forward circuit involving the hypothalamus, stomach fundus and fat depots. Presentation: 6/3/2024

Associations between parental rearing style and amygdala and hippocampal subfield abnormalities in drug-naive females with anorexia nervosa

BackgroundAltered volumes in the hippocampus and amygdala have been linked to anorexia nervosa (AN). This study aimed to investigate amygdala and hippocampal subfields volume abnormalities in AN patients, and their associations with parental rearing practices and clinical psychological characteristics.MethodsThis study included twenty-nine drug-naive females with AN from West China Hospital of Sichuan University, China, and fifty-nine age- and gender-matched healthy controls (HCs) recruited through advertisement. All participants underwent T1-weighted imaging. Amygdala and hippocampal subfields volume was calculated using FreeSurfer 7.0. The Core Self-Evaluation Scale (CSES) and Rosenberg Self-Esteem Scale (RSES) were used to assess the psychological characteristics of AN patients. The Egna Minnen av Barndoms Uppfostran (EMBU) was employed to evaluate parental rearing practices. Group differences in brain volumes were analyzed with covariates like age and total intracranial volume (TIV). Partial correlation analysis explored the correlations between brain region volumes and clinical psychological characteristics.ResultsAN patients exhibited lower RSES and CSES scores, and more adverse parental rearing style than healthy norms. After adjusting for covariates, AN patients showed decreased gray matter volume (GMV) in the left medial (Me) and cortical (Co) nucleus, as well as in the right hippocampal-amygdala transition area (HATA). GMV in the left Me was correlated with years of education among HCs but not among AN patients. GMV in the right HATA was positively correlated with paternal penalty and severity, as well as maternal overinterference.ConclusionThis study supports structure abnormalities in amygdala and hippocampus in AN patients and suggests that parental rearing practices may be associated with hippocampal abnormalities, potentially contributing to the pathophysiology of AN. Addressing appropriate parental rearing styles may offer a positive impact on AN.

Loss of C1q alters the auditory brainstem response.

Neural circuits in the auditory brainstem compute interaural time and intensity differences used to determine the locations of sound sources. These circuits display features that are specialized for these functions. The projection from the ventral cochlear nucleus (VCN) to the medial nucleus of the trapezoid (MNTB) body travels along highly myelinated fibers and terminates in the calyx of Held. This monoinnervating synapse emerges during development as multiple inputs are eliminated. We previously demonstrated that elimination of microglia with a colony stimulating factor-1 inhibitor results in impaired synaptic pruning so that multiple calyceal terminals reside on principal cells of MNTB. This inhibitor also resulted in impaired auditory brainstem responses (ABRs), with elevated thresholds and increased peak latencies. Loss of the microglial fractalkine receptor, CX3CR1, decreased peak latencies in the ABR. The mechanisms underlying these effects are not known. One prominent microglial signaling pathway involved in synaptic pruning and plasticity during development and aging is the C1q-initiated compliment cascade. Here we investigated the classical complement pathway initiator, C1q, in auditory brainstem maturation. We found that C1q expression is detected in the MNTB by the first postnatal week. C1q levels increased with age and were detected within microglia and surrounding the soma of MNTB principal neurons. Loss of C1q did not affect microglia-dependent calyceal pruning. Excitatory and inhibitory synaptic markers in the MNTB and LSO were not altered with C1q deletion. ABRs showed that C1q KO mice had normal hearing thresholds but shortened peak latencies. Altogether this study uncovers the developmental time frame of C1q expression in the sound localization pathway and shows a subtle functional consequence of C1q knockdown.

Microdosing of a kappa opioid receptor agonist within proximal nucleus accumbens shell microstructures revealing opposing behavioral outcomes

Targeted intracranial delivery of molecularly-specific therapies within intricate brain structures poses a formidable challenge due to the heterogeneity of neuronal phenotypes and functions. Here we report the use of an implantable, miniaturized neural drug delivery system permitting dynamic adjustment of pharmacotherapies. Specifically, we exploit the spatial accuracy afforded by this method for targeting modulation of neuronal microstructures. Kappa opioid receptors (KOR) within the dorsal medial nucleus accumbens shell (NASh) are selectively activated through micro infusions of the KOR agonist, U-50488. Remarkably, we demonstrate that micro infusions of U-50488 into the dorsal NASh induces reward-like conditioned place preferences, whereas a mere 1 mm shift ventrally results in conditioned place aversions. The striking precision afforded by this method may prove useful in other neurotherapeutic interventions.

The volumes of amygdala subregions and peripheral programmed cell death protein-1 levels are associated with cognitive decline in individuals with knee osteoarthritis.

Persistent pain is a prominent symptom of knee osteoarthritis (KOA) and has been associated with cognitive decline in individuals with KOA. The amygdala, a complex structure consisting of nine subnuclei, and programmed cell death protein-1 (PD-1) levels play crucial roles in pain regulation and cognitive processing. This study aims to investigate the relationships among amygdala subregion volumes, cognitive function, and PD-1 levels to elucidate the underlying mechanism of cognitive decline in KOA. In this cross-sectional study, we recruited 36 patients with KOA and 25 age/gender-matched healthy controls for neuropsychological tests, structural magnetic resonance imaging scanning, and measurement of serum PD-1 levels. We used the atlas provided by FreeSurfer software to automatically segment the amygdala subnuclei. Subsequently, we compared the volumes of amygdala subregions between groups and explored their correlation with clinical scores and PD-1 levels. Compared to healthy controls, individuals with KOA exhibited significantly lower scores on global cognition tasks, such as long-delay free recall, short-delay free recall, and immediate recall tasks. Moreover, they displayed decreased volumes in lateral nucleus basal nucleus paralaminar nucleus while showing increased volumes in accessory basal nucleus, central nucleus, medial nucleus, and cortical nucleus. Within the KOA group specifically, paralaminar volume was negatively correlated with immediate recall scores; pain scores were negatively correlated with global cognition; basal volume was negatively correlated with PD-1 levels. Our findings highlight those alterations in amygdala subregion volumes along with changes in serum PD-1 levels may contribute to observe cognitive decline among individuals suffering from KOA.

Abnormal developmental of hippocampal subfields and amygdalar subnuclei volumes in young adults with heavy cannabis use: A three-year longitudinal study

BackgroundDifferences in the volumes of the hippocampus and amygdala have consistently been observed between young adults with heavy cannabis use relative to their non-using counterparts. However, it remains unclear whether the subfields of these functionally and structurally heterogenous regions exhibit similar patterns of change in young adults with long-term heavy cannabis use disorder (CUD). ObjectivesThis study aims to investigate the effects of long-term heavy cannabis use in young adults on the subregional structures of the hippocampus and amygdala, as well as their longitudinal alterations. MethodsThe study sample comprised 20 young adults with heavy cannabis use and 22 matched non-cannabis using healthy volunteers. All participants completed the Cannabis Use Disorder Identification Test (CUDIT) and underwent two T1-structural magnetic resonance imaging (MRI) scans, one at baseline and another at follow-up 3 years later. The amygdala, hippocampus, and their subregions were segmented on T1-weighted anatomical MRI scans, using a previously validated procedure. ResultsAt baseline, young adults with heavy CUD exhibited significantly larger volumes in several hippocampal (bilateral presubiculum, subiculum, Cornu Ammonis (CA) regions CA1, CA2-CA3, and right CA4-Dentate Gyrus (DG)) and amygdala (bilateral paralaminar nuclei, right medial nucleus, and right lateral nucleus) subregions compared to healthy controls, but these differences were attenuated at follow-up. Longitudinal analysis revealed an accelerated volumetric decrease in these subregions in young adults with heavy CUD relative to controls. Particularly, compared to healthy controls, significant accelerated volume decreases were observed in the right hippocampal subfields of the parasubiculum, subiculum, and CA4-DG. In the amygdala, similar trends of accelerated volumetric decreases were observed in the left central nucleus, right paralaminar nucleus, right basal nucleus, and right accessory basal nucleus. ConclusionsThe current findings suggest that long-term heavy cannabis use impacts maturational process of the amygdala and hippocampus, especially in subregions with high concentrations of cannabinoid type 1 receptors (CB1Rs) and involvement in adult neurogenesis.

Anterior and posterior thalamic volumes differentially correlate with memory, attention, and motor processes in HIV infection and alcohol use disorder comorbidity

The thalamus, with its reciprocal connections to and from cortical, subcortical, and cerebellar regions, is a central active participant in multiple functional brain networks. Structural MRI studies measuring the entire thalamus without respect to its regional or nuclear divisions report volume shrinkage in diseases including HIV infection, alcohol use disorder (AUD), and their comorbidity (HIV+AUD). Here, we examined relations between thalamic subregions (anterior, ventral, medial, and posterior) and neuropsychological functions (attention/working memory, executive functioning, episodic memory, and motor skills). Volumes of thalamic subregions were derived from automatic segmentations of standard T1 weighted MRIs of 65 individuals with HIV, 189 with AUD, 80 with HIV+AUD comorbidity, and 141 healthy controls (CTRL). Total thalamic volume was smaller and cognitive and motor composite scores were lower in the three diagnostic groups relative to the CTRL group. The AUD and HIV+AUD groups had significantly smaller thalamic subregional volumes than the CTRL group. The HIV+AUD group had smaller anterior thalamic volume than the HIV-only group and smaller ventral thalamic volume than the AUD-only group. In the HIV+AUD group, memory scores correlated with anterior thalamic volumes, attention/working memory scores correlated with posterior and medial thalamic volumes, and motor skill scores correlated with posterior thalamic volumes. Exploratory analyses focused on the HIV+AUD group indicated that within the posterior thalamic region, the pulvinar and medial geniculate nuclei were related to attention/working memory scores, and the pulvinar was related to motor skills scores. This study is novel in locating volume deficits in specific thalamic subregions, in addition to the thalamus as a whole, in HIV, AUD, and their comorbidity and in identifying functional ramifications of these deficits. Taken together, this study highlights the relevance of thalamic subregional volume deficits to dissociable cognitive and motor processes.