Glucocorticoid receptor dysregulation underlies 5-HT2A receptor-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model

Prenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with poly-(I:C) as a mouse MIA model, we show that upregulation of the serotonin 5-HT2A receptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulated nuclear GR translocation in frontal cortex of schizophrenia subjects. Repeated (twice a day for 4 days) corticosterone administration augmented frontal cortex 5-HT2AR expression and reduced GR binding to the 5-HT2AR promoter. However, virally (AAV)-mediated augmentation of GR function reduced frontal cortex 5-HT2AR expression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT2AR expression in mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neurodevelopmental psychiatric disorders.

Neural changes after training with transcranial direct current stimulation to increase speech fluency in adults who stutter

In a randomised controlled trial, we showed that a five-day intervention combining anodal transcranial direct current stimulation over the left inferior frontal cortex with temporary speech fluency enhancing techniques reduces stuttering. Speech fluency was unchanged by the fluency training alone, as predicted. Here, we report the neural changes associated with the intervention, measured using functional MRI during sentence reading before the training and one-week later. We obtained imaging data in 25 adult men who stutter (median age = 32 y, inter-quartile range = 11) at the pre-intervention baseline and again one-week post-intervention. A control group of 15 adult men who do not stutter (median age = 30 y, inter-quartile range = 10) and did not complete the intervention were scanned on one occasion. In a whole-brain analysis of perceptibly fluent sentence reading, we compared the change in task-evoked neural activity in the sub-group of men who stutter who had received active stimulation during the intervention (N=13) with those who had sham stimulation (N=12). We hypothesised that the combination of anodal stimulation over the left inferior frontal cortex and fluency-enhancing training would result in lasting change to the brain networks supporting fluent speech production. An additional region-of-interest analysis explored effects on basal ganglia nuclei, which are thought to have a key role in the casual mechanism of stuttering, and which we hypothesised would be engaged by the behavioural approach used during training (choral and metronome-timed speaking). One week after the intervention, the group who had received active transcranial stimulation showed increased activity in speech-related brain regions, relative to the group who had received sham stimulation. Cortically, these changes were evident in left inferior frontal cortex (pars opercularis and orbitalis), anterior insula, anterior superior temporal gyrus, anterior cingulate cortex, and supplementary motor area. Subcortically, activation increased in the caudate nuclei and putamen bilaterally, and in right globus pallidus and thalamus. Together these regions form cortico-striatal-thalamo-cortical loops involved in the planning and initiation and control of speech movements.Our findings reveal that the mechanism of action of the tDCS intervention involved increasing activity across the network involved in the production of fluent speech, indicating that tDCS can be used to promote neural plasticity to strengthen networks supporting natural fluency. This study advances the potential of using non-invasive brain stimulation to improve therapy efficacy for those people who stutter who choose to work on increasing fluency.

From Retrospective to Prospective: Integrated Value Representation in Frontal Cortex for Predictive Choice Behavior

Animals must flexibly estimate the value of their actions to successfully adapt in a changing environment. The brain is thought to estimate action-value from two different sources, namely the action-outcome history (retrospective value) and the knowledge of the environment (prospective value). How these two different estimates of action-value are reconciled to make a choice is not well understood. Here we show that as a mouse learns the state-transition structure of a decision-making task, retrospective and prospective values become jointly encoded in the preparatory activity of neurons in the frontal cortex. Suppressing this preparatory activity in expert mice returned their behavior to a naive state. These results reveal the neural circuit that integrates knowledge about the past and future to support predictive decision-making.

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A Comparative Study of Koizumi and Longa Methods of Intraluminal Filament Middle Cerebral Artery Occlusion in Rats: Early Corticosterone and Inflammatory Response in the Hippocampus and Frontal Cortex

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed critical differences between them along with similarities (Smith et al. 2015; Morris et al. 2016). In this study, a direct comparison of MCAO-KM and MCAO-LM in rats was performed. Three days after MCAO, infarct volume, mortality rate, neurological deficit, and weight loss were similar in these models. MCAO-LM rats showed an increase in ACTH levels, while MCAO-KM rats demonstrated elevated corticosterone and interleukin-1β in blood serum. Corticosterone accumulation was detected in the frontal cortex (FC) and the hippocampus of the MCAO-KM group. IL1β beta increased in the ipsilateral hippocampus in the MCAO-KM group and decreased in the contralateral FC of MCAO-LM rats. Differences revealed between MCAO-KM and MCAO-LM suggest that corticosterone and interleukin-1β release as well as hippocampal accumulation is more expressed in MCAO-KM rats, predisposing them to corticosterone-dependent distant neuroinflammatory hippocampal damage. The differences between two models, particularly, malfunction of the hypothalamic–pituitary–adrenal axis, should be considered in the interpretation, comparison, and translation of pre-clinical experimental results.

Disrupting inferior frontal cortex activity alters affect decoding efficiency from clear but not from ambiguous affective speech

The evaluation of socio-affective sound information is accomplished by the primate neural auditory cortex in collaboration with limbic and inferior frontal brain nodes. For the latter, activity in inferior frontal cortex (IFC) is often observed during classification of voice sounds, especially if they carry affective information. Partly opposing views have been proposed, with IFC either coding cognitive processing challenges in case of sensory ambiguity or representing categorical object and affect information for clear vocalizations. Here, we presented clear and ambiguous affective speech to two groups of human participants during neuroimaging, while in one group we inhibited right IFC activity with transcranial magnetic stimulation (TMS) prior to brain scanning. Inhibition of IFC activity led to partly faster affective decisions, more accurate choice probabilities and reduced auditory cortical activity for clear affective speech, while fronto-limbic connectivity increased for clear vocalizations. This indicates that IFC inhibition might lead to a more intuitive and efficient processing of affect information in voices. Contrarily, normal IFC activity might represent a more deliberate form of affective sound processing (i.e., enforcing cognitive analysis) that flags categorial sound decisions with precaution (i.e., representation of categorial uncertainty). This would point to an intermediate functional property of the IFC between previously assumed mechanisms.

Processing human frontal cortex brain tissue for population-scale Oxford Nanopore long-read DNA sequencing SOP v1

Processing human frontal cortex brain tissue for population-scale Oxford Nanopore long-read DNA sequencing SOP At the NIH's Center for Alzheimer's and Related Dementias (CARD) https://card.nih.gov/research-programs/long-read-sequencing we will generate long-read sequencing data from roughly 4000 patients with Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and healthy subjects. With this research, we will build a public resource consisting of long-read genome sequencing data from a large number of confirmed people with Alzheimer's disease and related dementias and healthy individuals. To generate this large-scale nanopore sequencing data we have developed a protocol for processing and long-read sequencing human frontal cortex brain tissue, targeting an N50 of ~30kb and ~30X coverage. †Correspondence to: Kimberley Billingsley [email protected] and Cornelis Blauwendraat [email protected] Acknowledgements: We would like to thank the Nanopore team (Androo Markham &Hannah Lucio), Circulomics Inc team (Jeffrey Burke, Michelle Kim, Duncan Kilburn & Kelvin Liu) and the whole CARD long-read team listed below => UCSC: Benedict Paten, Mikhail Kolmogorov, Miten Jain, Kishwar Shafin, Trevor Pesout; NHGRI: Adam Phillippy, Arang Rhie; Baylor: Fritz Sedlazeck; JHU: Winston Timp; NINDS: Sonja Scholz; NIA: Cornelis Blauwendraat, Kimberley Billingsley, Frank Grenn, Pilar Alvarez Jerez, Bryan Traynor, Shannon Ballard, Caroline Pantazis; CZI: Paolo Carnevali.

Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms

CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 μM and Ki = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.