Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome.

GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L-glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4. Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.

Novel role of NCoR1 in impairing spatial memory through the mediation of a novel interacting protein DEC2.

Long-term memory formation requires de novo RNA and protein synthesis. Using differential display PCR, we found that the NCoR1 cDNA fragment is differentially expressed between fast learners and slow learners, with fast learners showing a lower expression level than slow learners in the water maze learning task. Fast learners also show lower NCoR1 mRNA and protein expression levels. In addition, spatial training decreases both NCoR1 mRNA and protein expression, whereas NCoR1 conditional knockout (cKO) mice show enhanced spatial memory. In studying the molecular mechanism, we found that spatial training decreases the association between NCoR1 and DEC2. Both NCoR1 and DEC2 suppress the expression of BDNF, integrin α3 and SGK1 through C/EBPα binding to their DNA promoters, but overexpression of DEC2 in NCoR1 cKO mice rescues the decreased expression of these proteins compared with NCoR1 loxP mice overexpressing DEC2. Further, spatial training decreases DEC2 expression. Spatial training also enhances C/EBPα binding to Bdnf, Itga3 and Sgk1 promoters, an effect also observed in fast learners, and both NCoR1 and DEC2 control C/EBPα activity. Whereas knockdown of BDNF, integrin α3 or SGK1 expression impairs spatial learning and memory, it does not affect Y-maze performance, suggesting that BDNF, integrin α3 and SGK1 are involved in long-term memory formation, but not short-term memory formation. Moreover, NCoR1 expression is regulated by the JNK/c-Jun signaling pathway. Collectively, our findings identify DEC2 as a novel interacting protein of NCoR1 and elucidate the novel roles and mechanisms of NCoR1 and DEC2 in negative regulation of spatial memory formation.

Deep behavioural phenotyping of the Q175 Huntington disease mouse model: effects of age, sex, and weight.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. RESULTS: In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. CONCLUSIONS: Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.

Regulation of the Ca2+ Channel CaV1.2 Supports Spatial Memory and Its Flexibility and LTD.

Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The ß2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca2+ channel (LTCC) CaV1.2. Phosphorylation of CaV1.2 by PKA on Ser1928 is required for the upregulation of Ca2+ influx on ß2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by ß2 AR antagonists and peptides that displace ß2 AR from CaV1.2. This work identifies CaV1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca2+ channel CaV1.2 on Ser1928 is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.

Electronic Cigarette Vape Exposure Exacerbates Post-Ischemic Outcomes in Female but Not in Male Rats.

BACKGROUND: Nicotine-containing electronic cigarette (EC) vaping has become popular worldwide, and our understanding of the effects of vaping on stroke outcomes is elusive. Using a rat model of transient middle cerebral artery occlusion, the current exploratory study aims to evaluate the sex-dependent effects of EC exposure on brain energy metabolism and stroke outcomes. METHODS: Adult Sprague-Dawley rats of both sexes were randomly assigned to air/EC vapor (5% nicotine Juul pods) exposure for 16 nights, followed by randomization into 3 cohorts. The first cohort underwent exposure to air/EC preceding randomization to transient middle cerebral artery occlusion (90 minutes) or sham surgery, followed by survival for 21 days. During the survival period, rats underwent sensorimotor and Morris water maze testing. Subsequently, brains were collected for histopathology. A second cohort was exposed to air/EC after which brains were collected for unbiased metabolomics analysis. The third cohort of animals was exposed to air/EC and received transient middle cerebral artery occlusion/sham surgery, and brain tissue was collected 24 hours later for biochemical analysis. RESULTS: In females, EC significantly increased (P<0.05) infarct volumes by 94% as compared with air-exposed rats, 165±50 mm3 in EC-exposed rats, and 85±29 mm3 in air-exposed rats, respectively, while in males such a difference was not apparent. Morris water maze data showed significant deficits in spatial learning and working memory in the EC sham or transient middle cerebral artery occlusion groups compared with the respective air groups in rats of both sexes (P<0.05). Thirty-two metabolites of carbohydrate, glycolysis, tricarboxylic acid cycle, and lipid metabolism were significantly altered (P≤0.05) due to EC, 23 of which were specific for females. Steady-state protein levels of hexokinase significantly decreased (P<0.05) in EC-exposed females; however, these changes were not seen in males. CONCLUSIONS: Even brief EC exposure over 2 weeks impacts brain energy metabolism, exacerbates infarction, and worsens poststroke cognitive deficits in working memory more in female than male rats.

Validity and value of metabolic connectivity in mouse models of ß-amyloid and tauopathy.

Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (ß-amyloid and tau) by use of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas ß-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different ß-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

Temporal and region-specific tau hyperphosphorylation in the medulla and forebrain coincides with development of functional changes in male obese Zucker rats.

Metabolic syndrome (MetS) is associated with development of tauopathies that contribute to cognitive decline. Without functional leptin receptors, male obese Zucker rats (OZRs) develop MetS, and they have increased phosphorylated tau (ptau) with impaired cognitive function. In addition to regulating energy balance, leptin enhances activation of the hippocampus, which is essential for spatial learning and memory. Whether spatial learning and memory are always impaired in OZRs or develop with MetS is unknown. We hypothesized that male OZRs develop MetS traits that promote regional increases in ptau and functional deficits associated with those brain regions. In the medulla and cortex, tau-pSer199,202 and tau-pSer396 were comparable in juvenile (7-8 wk old) lean Zucker rats (LZRs) and OZRs but increased in 18- to 19-wk-old OZRs. Elevated tau-pSer396 was concentrated in the dorsal vagal complex of the medulla, and by this age OZRs had hypertension with increased arterial pressure variability. In the hippocampus, tau-pSer199,202 and tau-pSer396 were still comparable in 18- to 19-wk-old OZRs and LZRs but elevated in 28- to 29-wk-old OZRs, with emergence of deficits in Morris water maze performance. Comparable escape latencies observed during acquisition in 18- to 19-wk-old OZRs and LZRs were increased in 28- to 29-wk-old OZRs, with greater use of nonspatial search strategies. Increased ptau developed with changes in the insulin/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in the hippocampus and cortex but not medulla, suggesting different underlying mechanisms. These data demonstrate that leptin is not required for spatial learning and memory in male OZRs. Furthermore, early development of MetS-associated autonomic dysfunction by the medulla may be predictive of later hippocampal dysfunction and cognitive impairment.NEW & NOTEWORTHY Male obese Zucker rats (OZRs) lack functional leptin receptors and develop metabolic syndrome (MetS). At 16-19 wk, OZRs are insulin resistant, with increased ptau in dorsal medulla and impaired autonomic regulation of AP. At 28-29 wk OZRs develop increased ptau in hippocampus with deficits in spatial learning and memory. Juvenile OZRs lack elevated ptau and these deficits, demonstrating that leptin is not essential for normal function. Elevated ptau and deficits emerge before the onset of diabetes in insulin-resistant OZRs.

Object-place-context learning impairment correlates with spatial learning impairment in aged Long-Evans rats.

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases. In the Morris water maze, aged memory-unimpaired (AU) rats navigate to remembered goal locations as effectively as young rats and demonstrate minimal alterations in physiological markers of synaptic plasticity, whereas aged memory-impaired (AI) rats show impairments in both spatial navigation skills and cellular and molecular markers of plasticity. The present study investigates whether another cognitive domain is affected similarly to navigation in aged Long-Evans rats. We tested the ability of young, AU, and AI animals to recognize novel object-place-context (OPC) configurations and found that performance on the novel OPC recognition paradigm was significantly correlated with performance on the Morris water maze. In the first OPC test, young and AU rats, but not AI rats, successfully recognized and preferentially explored objects in novel OPC configurations. In a second test with new OPC configurations, all age groups showed similar OPC associative recognition memory. The results demonstrated similarities in the behavioral expression of associative, episodic-like memory between young and AU rats and revealed age-related, individual differences in functional decline in both navigation and episodic-like memory abilities.

Effects of high-intensity chronic noise on spatial memory in male versus female rats.

The detrimental effects of high-intensity noise on the auditory system and emotional status, including the induction of anxiety, are well documented. Preclinical as well as epidemiological and clinical studies have solidly established differential responses between males and females to various stressful stimuli, including high-intensity white noise (HIWN). However, whether chronic exposure to noise affects cognitive functions and whether this effect is sex dependent has not been adequately addressed. In this study, we used two cognitive test paradigms, such as the Morris water maze (MWM) and the multi-branch maze (MBM), to test the effect of chronic HIWN on indices of spatial learning and memory in both male and female Wistar rats. Our findings indicate that daily (1 h) exposure to 100 dB of noise for 30 consecutive days induces different task-dependent responses in male versus female rats. For example, in the acquisition phase of MWM, female rats exposed to noise outperformed their male counterparts at twice the speed. Similarly, in the MBM test, noise-exposed female rats outperformed the male rats in reaching the nest box. It is clear from these studies that noise impairs cognitive functions twice as negatively in male rats as in female rats. Thus, sex-related differences in spatial learning and memory in response to HIWN must be taken into consideration when investigating the neurobiological components and/or treatment modalities.

DNA binding reveals hidden interdomain allostery of a MazE antitoxin from Mycobacterium tuberculosis.

Type II toxin-antitoxin (TA) systems are ubiquitously distributed genetic elements in prokaryotes and are crucial for cell maintenance and survival under environmental stresses. The antitoxin is a modular protein consisting of the disordered C-terminal region that physically contacts and neutralizes the cognate toxin and the well-folded N-terminal DNA binding domain responsible for autorepression of TA transcription. However, how the two functional domains communicate is largely unknown. Herein, we determined the crystal structure of the N-terminal domain of the type II antitoxin MazE-mt10 from Mycobacterium tuberculosis, revealing a homodimer of the ribbon-helix-helix (RHH) fold with distinct DNA binding specificity. NMR studies demonstrated that full-length MazE-mt10 forms the helical and coiled states in equilibrium within the C-terminal region, and that helical propensity is allosterically enhanced by the N-terminal binding to the cognate operator DNA. This coil-to-helix transition may promote toxin binding/neutralization of MazE-mt10 and further stabilize the TA-DNA transcription repressor. This is supported by many crystal structures of type II TA complexes in which antitoxins form an α-helical structure at the TA interface. The hidden helical state of free MazE-mt10 in solution, favored by DNA binding, adds a new dimension to the regulatory mechanism of type II TA systems. Furthermore, complementary approaches using X-ray crystallography and NMR allow us to study the allosteric interdomain interplay of many other full-length antitoxins of type II TA systems.

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Learning the native pond odor as one of the mechanisms of olfactory orientation in juvenile smooth newt Lissotriton vulgaris.

Olfaction is an important mechanism of orientation in amphibians toward the breeding site. It is known that anurans can memorize the odor of the native pond during larval development and prefer this odor prior to the beginning of dispersion. However, such a mechanism in urodeles has not been studied yet. We conducted experiments on recognition of the odor of a native water body in juveniles of the smooth newt Lissotriton vulgaris. One group of larvae were reared in pure water (control), the other group in water with morpholine (10-7 mol/L). A few days after metamorphosis, the newts were tested under paired-choice conditions in a T-maze. A total of 73 newts from the experimental group and 47 newts from the control group were tested. The results of the experiment show that the newts in the experimental group preferred the morpholine solution, whereas the individuals of the control group made the choice randomly. We conclude that newts can learn the odor of the environment in which they developed and use this memory for orientation in later stages of life.

Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety.

Letrozole, an aromatase inhibitor preventing estrogen synthesis from testosterone, is used as an adjuvant therapy in estrogen receptor-positive breast cancer patients. However, like other aromatase inhibitors, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here, we studied the effects of chronic letrozole treatment on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies, to develop an appropriate animal model aimed at testing therapies to mitigate side effects of letrozole. In Morris water maze, letrozole 0.1 mg/kg impaired reference learning and memory. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation, but rather delayed acquisition of spatial information. The delay might be related to increased anxiety as suggested by increased thigmotactic behavior during the reference memory training. The learning impairment was water maze-specific since we did not observe impairment in other spatial tasks such as in Y-maze or object location test. In contrast, the dose of 0.3 mg/kg did not have effect on water maze learning and facilitated locomotor habituation and recognition in novel object recognition test. The current study shows that letrozole dose-dependently modulates behavioral response and that its effects are task-dependent.

Female mice lacking membrane estrogen receptor alpha display impairments in spatial memory.

Estrogens exert effects on cognition by acting on estrogen receptors (ER) including ERα. Activation of nuclear ERα results in classical genomic signaling leading to transcriptional changes that occur over hours to days. In contrast, activation of ERα localized to the membrane results in rapid signaling with effects occurring in seconds to minutes. The goal of the current study was to determine the role of membrane ERα in spatial memory. Female wildtype (WT) and transgenic mice that lack membrane ERα and express nuclear only ERα (NOER) were trained on an eight-arm radial-maze task. Following training, mice were tested on delay trials, in which delays ranging from 30 min to 5 h were inserted between the 4th and 5th arm choices. Performance was measured by number of proactive and retroactive errors. Proactive errors are short-term working memory errors defined by reentries into arms previously visited during the post-delay period or errors made during the pre-delay period. Retroactive errors are delay-dependent memory errors, defined as reentries into arms during the post-delay that were previously visited during the pre-delay. Consistent with a role for membrane ERα in rapid signaling, NOER mice made more proactive errors than WTs across all delays. NOER mice made more retroactive errors than WTs only after the 5-h delay. WT and NOER mice performed similarly on elevated plus maze and open field tests indicating no effects of membrane ERα on anxiety-related behavior or locomotor activity. Results reveal that membrane ERα plays important roles in both short-term and longer-term delay-dependent memory either directly or potentially indirectly through a role in the regulation of estradiol levels via the hypothalamic-pituitary-gonadal axis.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Subregion specific neuroadaptations in the female rat striatum during acute and protracted withdrawal from nicotine.

Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain. To this end, female rats received 15 injections of either nicotine (0.36mg/kg) or saline, over a 3-week period and were then followed for up to 3 months. Behavioral effects of nicotine were assessed using locomotor activity measurements and elevated plus maze, while neurophysiological changes were monitored using ex vivo electrophysiological field potential recordings conducted in subregions of the dorsal and ventral striatum. Behavioral assessments demonstrated a robust sensitization to the locomotor stimulatory properties of nicotine, but monitored behaviors on the elevated plus maze were not affected during acute (24 h) or protracted (3 months) withdrawal. Electrophysiological recordings revealed a selective increase in excitatory neurotransmission in the nucleus accumbens shell and dorsomedial striatum during acute withdrawal. Importantly, accumbal neuroadaptations in nicotine-treated rats correlated with locomotor behavior, supporting a role for the nucleus accumbens in behavioral sensitization. While no sustained neuroadaptations were observed following 3 months withdrawal, there was an overall trend towards reduced inhibitory tone. Together, these findings suggest that nicotine produces selective transformations of striatal brain circuits that may drive specific behaviors associated with nicotine exposure. Furthermore, our observations suggest that sex-specificity should be considered when evaluating long-term effects by nicotine on the brain.

Acromegalic Rat Model Presented Cognitive Impairments and Tau Hyperphosphorylation in the Hippocampus.

INTRODUCTION: Acromegaly patients, in addition to the most prominent physical and endocrine changes, also exhibit a higher risk of cognitive dysfunction. However, the reasons and mechanisms underlying cognitive impairments in acromegaly patients remain unknown. METHODS: Acromegalic rats were induced by subcutaneous injection of tumor cells, with continuous monitoring of the body weight and hormones to confirm the occurrence of acromegaly. Behavioral assessments, including open field test, novel object recognition test, and Barnes maze test, were conducted to evaluate the animals' cognitive function. Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to examine changes in the hippocampal tau protein, Aß, and associated signaling pathways. RESULTS: The tumor cells secreting growth hormone increased the secretion of growth hormone, resulting in changes in body size and endocrine functions, thus causing acromegaly. The acromegaly model showed deficiencies in working memory and spatial memory. Hyperphosphorylation of tau protein was observed in the hippocampus of the acromegaly model, but no Aß deposition was observed. The acromegaly model exhibits hippocampal growth hormone (GH) resistance, decreased expression of GH receptors, and subsequently reduced expression activity of the PI3K-Akt-GSK3ß signaling pathway, which is responsible for the hyperphosphorylation of tau protein. CONCLUSION: The prolonged elevation of GH and insulin-like growth factor 1 caused by acromegaly may lead to abnormalities in the SD rat's PI3K-Akt-GSK3ß signaling pathway, subsequently resulting in hyperphosphorylation of the hippocampal tau protein and cognitive impairment.

Effect and Potential Mechanism of Immunotherapy on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses. RESULTS: After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aß40, Aß42, and Tau levels, as well as increasing IL-4 levels. CONCLUSION: Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.

Role of the medial agranular cortex in unilateral spatial neglect.

Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among various positions of the lesions, the recovery from USN during recovery periods (postoperative day; POD 10-18) tended to be slower in cases with more rostral lesions in the AGm (r = - 0.302; p = 0.028). Moreover, the total number of arm entries and maximum moving speed did not significantly differ between before and after AGm infarction. According to these results, the anterior lesions may slowly recover from USN-like behavior, and there may be a weak association between the AGm infarct site and recovery rate. In addition, all unilateral focal infarctions in the AGm induced USN-like behavior without motor deficits.

Sequential hybrid ablation vs. surgical CryoMaze alone for treatment of atrial fibrillation: results of multicentre randomized controlled trial.

AIMS: Data on the hybrid atrial fibrillation (AF) treatment are lacking in patients with structural heart disease undergoing concomitant CryoMaze procedures. The aim was to assess whether the timely pre-emptive catheter ablation would achieve higher freedom from AF or atrial tachycardia (AT) and be associated with better clinical outcomes than surgical ablation alone. METHODS AND RESULTS: The trial investigated patients with non-paroxysmal AF undergoing coronary artery bypass grafting and/or valve repair/replacement with mandatory concomitant CryoMaze procedure who were randomly assigned to undergo either radiofrequency catheter ablation [Hybrid Group (HG)] or no further treatment (Surgery Group). The primary efficacy endpoint was the first recurrence of AF/AT without class I or III antiarrhythmic drugs as assessed by implantable cardiac monitors. The primary clinical endpoint was a composite of hospitalization for arrhythmia recurrence, worsening of heart failure, cardioembolic event, or major bleeding. We analysed 113 and 116 patients in the Hybrid and Surgery Groups, respectively, with a median follow-up of 715 (IQR: 528-1072) days. The primary efficacy endpoint was significantly reduced in the HG [41.1% vs. 67.4%, hazard ratio (HR) = 0.38, 95% confidence interval (CI): 0.26-0.57, P < 0.001] as well as the primary clinical endpoint (19.9% vs. 40.1%, HR = 0.51, 95% CI: 0.29-0.86, P = 0.012). The trial groups did not differ in all-cause mortality (10.6% vs. 8.6%, HR = 1.17, 95%CI: 0.51-2.71, P = 0.71). The major complications of catheter ablation were infrequent (1.9%). CONCLUSION: Pre-emptively performed catheter ablation after the CryoMaze procedure was safe and associated with higher freedom from AF/AT and improved clinical outcomes.