-
Cell Reports Jul 2020Odors are well known to elicit strong emotional and behavioral responses that become strengthened throughout learning, yet the specific cellular systems involved in odor...
Odors are well known to elicit strong emotional and behavioral responses that become strengthened throughout learning, yet the specific cellular systems involved in odor learning and the direct influence of these on behavior are unclear. Here, we investigate the representation of odor-reward associations within two areas recipient of dense olfactory input, the posterior piriform cortex (pPCX) and the olfactory tubercle (OT), using electrophysiological recordings from mice engaged in reward-based learning. Neurons in both regions represent conditioned odors and do so with similar information content, yet the proportion of neurons recruited by conditioned rewarded odors and the magnitudes and durations of their responses are greater in the OT. Using fiber photometry, we find that OT D1-type dopamine-receptor-expressing neurons flexibly represent odors based on reward associations, and using optogenetics, we show that these neurons influence behavioral engagement. These findings contribute to a model whereby OT D1 neurons support odor-guided motivated behaviors.
Topics: Animals; Behavior, Animal; Male; Mice, Inbred C57BL; Neural Pathways; Neurons; Olfactory Tubercle; Piriform Cortex; Receptors, Dopamine D1; Reward; Smell
PubMed: 32697986
DOI: 10.1016/j.celrep.2020.107919 -
Nature Communications Jul 2020The learning of stimulus-outcome associations allows for predictions about the environment. Ventral striatum and dopaminergic midbrain neurons form a larger network for...
The learning of stimulus-outcome associations allows for predictions about the environment. Ventral striatum and dopaminergic midbrain neurons form a larger network for generating reward prediction signals from sensory cues. Yet, the network plasticity mechanisms to generate predictive signals in these distributed circuits have not been entirely clarified. Also, direct evidence of the underlying interregional assembly formation and information transfer is still missing. Here we show that phasic dopamine is sufficient to reinforce the distinctness of stimulus representations in the ventral striatum even in the absence of reward. Upon such reinforcement, striatal stimulus encoding gives rise to interregional assemblies that drive dopaminergic neurons during stimulus-outcome learning. These assemblies dynamically encode the predicted reward value of conditioned stimuli. Together, our data reveal that ventral striatal and midbrain reward networks form a reinforcing loop to generate reward prediction coding.
Topics: Animals; Dopamine; Dopaminergic Neurons; Male; Mesencephalon; Mice; Models, Theoretical; Olfactory Tubercle; Ventral Striatum
PubMed: 32651365
DOI: 10.1038/s41467-020-17257-7 -
The International Journal of... Apr 2024The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The... (Review)
Review
The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors, apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine, and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at the highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.
Topics: Antipsychotic Agents; Humans; Animals; Schizophrenia; Islands of Calleja; Neurogenesis
PubMed: 38629703
DOI: 10.1093/ijnp/pyae018 -
Proceedings of the National Academy of... Dec 2019Brain infection by the parasite in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense...
Brain infection by the parasite in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2Ly6C) and patrolling (CX3CR1Ly6C) monocytes into the blood and brain during infection of C57BL/6J and CCR2CX3CR1 mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood-brain barrier (BBB) within 2 wk of infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact -infected brains using iDISCO and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., 445:168-176 (2007)] indicated a consistent pattern of monocyte infiltration during infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during CNS infection.
Topics: Animals; Antigens, Ly; Blood-Brain Barrier; Brain; CX3C Chemokine Receptor 1; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Monocytes; Receptors, CCR2; Toxoplasmosis
PubMed: 31727842
DOI: 10.1073/pnas.1915778116 -
Frontiers in Neuroanatomy 2020Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD)....
Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area.
Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudate-putamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.
PubMed: 32581730
DOI: 10.3389/fnana.2020.00029 -
Scientific Reports Oct 2019Hypoparathyroidism remains one of the most common complications in thyroid surgery. This study aims for an improved understanding of the complexity of the blood supply...
Hypoparathyroidism remains one of the most common complications in thyroid surgery. This study aims for an improved understanding of the complexity of the blood supply and the localisation of the parathyroids compared to the two most important intraoperative landmarks: the inferior laryngeal nerve (ILN) and Zuckerkandl's tubercle (ZT). We examined 103 laryngeal compounds to classify the blood supply and the localisation of the parathyroids. For intraoperative localisation we defined a Cartesian coordinate system with the ZT plane as x-axis and the course of the inferior laryngeal nerve as y-axis. The inferior thyroid artery (ITA) mainly supplies the parathyroids, whereas the superior thyroid artery provides a backup supply. It must be pointed out that 8.2% of parathyroids receive their blood directly from the thyroid gland. 73.5% of all parathyroids lie within 1 cm of the ILN and 1 cm cranial and 2.5 cm caudal to the ZT plane. Our described perimeters mark the most crucial areas during surgery and provide the surgeon with an anatomic mapping showing areas of special carefulness needed. One should keep bearing in mind all possible blood supply types of the parathyroids and therefore all branches should be handled with care.
Topics: Female; Humans; Hypoparathyroidism; Larynx; Male; Olfactory Tubercle; Parathyroid Glands; Postoperative Complications; Recurrent Laryngeal Nerve; Thyroid Gland; Thyroidectomy
PubMed: 31666619
DOI: 10.1038/s41598-019-52189-3 -
Progress in Neurobiology Sep 2019In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoguanine DNA glycosylase minimize 8-oxoguanine accumulation in genomic DNA. We investigated...
In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoguanine DNA glycosylase minimize 8-oxoguanine accumulation in genomic DNA. We investigated age-related alterations in behavior, 8-oxoguanine levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-Oxoguanine accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoguanine accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that newborn neurons from SVZ maintain ICjM in the adult brain, and increased accumulation of 8-oxoguanine in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age.
Topics: Aging; Animals; Cell Proliferation; DNA Repair Enzymes; Dentate Gyrus; Female; Islands of Calleja; Mice, Transgenic; Neurogenesis; Neurons; Phenotype; Phosphoric Monoester Hydrolases; Sex Characteristics
PubMed: 31026482
DOI: 10.1016/j.pneurobio.2019.04.002