Working Memory Behavior Research Articles

Chronic Stress Alters Synaptic Inhibition/Excitation Balance of Pyramidal Neurons But Not PV Interneurons in the Infralimbic and Prelimbic Cortices of C57BL/6J Mice.

The medial prefrontal cortex (mPFC) plays a pivotal role in regulating working memory, executive function, and self-regulatory behaviors. Dysfunction in the mPFC circuits is a characteristic feature of several neuropsychiatric disorders including schizophrenia, depression, and post-traumatic stress disorder. Chronic stress (CS) is widely recognized as a major triggering factor for the onset of these disorders. Although evidence suggests synaptic dysfunction in mPFC circuits following CS exposure, it remains unclear how different neuronal populations in the infralimbic (IL) and prelimbic (PL) cortices are affected in terms of synaptic inhibition/excitation balance (I/E ratio). Here, using neuroproteomic analysis and whole-cell patch-clamp recordings in pyramidal neurons (PNs) and parvalbumin (PV) interneurons within the PL and IL cortices, we examined the synaptic changes after 21 d of chronic unpredictable stress, in male mice. Our results reveal distinct impacts of CS on PL and IL PNs, resulting in an increased I/E ratio in both subregions but through different mechanisms: CS increases inhibitory synaptic drive in the PL while decreasing excitatory synaptic drive in the IL. Notably, the I/E ratio and excitatory and inhibitory synaptic drive of PV interneurons remained unaffected in both PL and IL circuits following CS exposure. These findings offer novel mechanistic insights into the influence of CS on mPFC circuits and support the hypothesis of stress-induced mPFC hypofunction.

Long-term exposure to ionic liquid [C8mim]Br induces the potential risk of anxiety and memory deterioration through disturbing neurotransmitter systems

1-octyl-3-methylimidazolium bromide ([C8mim]Br), one of the ionic liquids (ILs), has been used in various fields as an alternative green solvent of conventional organic solvents. Increased application and stabilization of imidazole ring structure lead to its release into the aquatic environment and long-term retention. Structure-activity relationship consideration suggested that ILs may be acetylcholinesterase inhibitors; however, neurotoxicity in vivo, especially the underlying mechanisms is rarely studied. In this study, the zebrafish were exposed to 2.5–10 mg/L [C8mim]Br for 28 days to comprehensively evaluate the neurotoxicity of ILs on adult zebrafish from the behavioral profiles and neurotransmitter systems for the first time. The results indicate that zebrafish exhibit suppressed spatial working memory and anxious behaviors. To assess the potential neurotoxic mechanisms underlying the behavioral responses of zebrafish, we measured the levels of neurotransmitters and precursors, key enzyme activities, and expression levels of relevant genes. Nissl staining showed significant neural cell death in zebrafish after 28-day [C8mim]Br exposure, with corresponding decreases in the levels of neurotransmitters (acetylcholine, glutamate, 5-hydroxytryptophan, gamma-aminobutyric acid, dopamine, and norepinephrine). Furthermore, these results were associated with mRNA expression levels of the disrupted neurotransmitter key genes (th, tph2, mao, slc6a3, ache, gad67). Overall, our study determined that [C8mim]Br caused potential mental disorders like anxiety and memory deterioration in zebrafish by impairing neurotransmitter systems, providing recommendations for the industrial production and application of [C8mim]Br.

Dexmedetomidine-mediated improvement of perioperative neurocognitive disorders by miR-184-3p-mediated NLRP3

BackgroundPerioperative neurocognitive disorders (PND) is a neurological complication in the perioperative period, which may lead to severe poor prognosis. Dexmedetomidine (Dex) is a commonly used sedative in the perioperative period. However, the effect of intraoperative anesthetic Dex on PND remains complicated and confusing. MethodsPND model was established using aged male mice, treated with Dex, and subjected to behavioral tests. The effect of Dex on pyroptosis was assessed by western blot, enzyme-linked immunosorbent assay and immunofluorescence. In addition, the miRNA expression profile of PND mice was identified by small RNA sequencing and performed PCR to detect miRNAs. Finally, the effect of miRNA on mice neuron pyroptosis was verified in vitro. ResultsWe found postoperative cognitive was declined in PND mice compared with control group, while preoperative injection of Dex improved short-term working memory and anxious exploration behavior, alleviated the cognitive impairment. Intriguingly, Dex ameliorated hippocampal inflammation and neuron pyroptosis in PND mice as evidenced by the reduced GSDMD, NLRP3, IL-1β and IL-18. The miRNA expression profile of PND mice hippocampus was disordered, including 5 miRNAs up-regulated and 17 miRNAs down-regulated, compared to the sham group. Dysregulated miRNAs were mainly enriched in biological functions related to neuronal development and signaling pathways related to pyroptosis. MiR-184-3p was the key miRNA, overexpression of miR-184-3p blocked the inhibitory effect of Dex on neuron pyroptosis, which was manifested as increased expression of GSDMD and NLRP3, increased inflammatory factors IL-1β and IL-18. ConclusionsThis study revealed that miR-184-3p may mediate NLRP3 to prevent the alleviating effect of Dex on PND, which provides a new potential way to improve the therapeutic intervention of PND.

CGRP as a potential mediator for the sexually dimorphic responses to traumatic brain injury

BackgroundThe outcomes of traumatic brain injury (TBI) exhibit variance contingent upon biological sex. Although female sex hormones exert neuroprotective effects, the administration of estrogen and progesterone has not yielded conclusive results. Hence, it is conceivable that additional mediators, distinct from female sex hormones, merit consideration due to their potential differential impact on TBI outcomes. Calcitonin gene-related peptide (CGRP) exhibits sexually dimorphic expression and demonstrates neuroprotective effects in acute brain injuries. In this study, we aimed to examine sex-based variations in TBI structural and functional outcomes with respect to CGRP expression.MethodsMale and female Sprague Dawley rats were exposed to controlled cortical impact to induce severe TBI, followed by interventions with and without CGRP inhibition. In the acute phase of TBI, the study centered on elucidating the influence of CGRP on oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and endothelial nitric oxide synthase (eNOS) signaling in the peri-impact tissue. Subsequently, during the chronic phase of TBI, the investigation expanded to evaluate CGRP expression in relation to lesion volume, microvascular dysfunction, and white matter injury, as well as working and spatial memory, anxiety-like, and depression-like behaviors in subjects of both sexes.ResultsFemale rats exhibited elevated levels of CGRP in the peri-impact brain tissue during both baseline conditions and in the acute and chronic phases of TBI, in comparison to age-matched male counterparts. Enhanced CGRP levels in specific brain sub-regions among female rats correlated with superior structural and functional outcomes following TBI compared to their male counterparts. CGRP inhibition induced heightened oxidative stress and a reduction in the expression of Nrf2 and eNOS in both male and female rats, with the observed alteration being more pronounced in females than in males.ConclusionsThis study marks the inaugural identification of CGRP as a downstream mediator contributing to the sexually dimorphic response observed in TBI outcomes.

196 Quantifying Cholinergic Cortical Response to Deep Brain Stimulation in Murine Models

INTRODUCTION: Deep brain stimulation has become a potential treatment for mental disorders. We have previously documented that chronic, one-hour daily, intermittent stimulation of the basal forebrain causes increases in cortical levels of acetylcholine and demonstrates improvement in working memory behavior in monkeys and mice. Continuous stimulation, in contrast, appears to deplete releasable acetylcholine in roughly one minute (Blake et al., Brain Stimulation, 2023; 16(1): 364). This study serves as the first quantification of cortical acetylcholine response to stimulation. METHODS: Viral vectors encoding cell surface receptors fluorescent to acetylcholine are injected into superficial cortex in mice through a small craniotomy. After three weeks, the craniotomy is enlarged for glass window affixation above the injection site. Electrodes are implanted posteriorly and angled to contact the basal forebrain. Cortical expression of acetylcholine in response to stimulation is visualized via two-photon microscopy through the window and quantified over time. RESULTS: Preliminary data suggest that the physiologic half-life of acetylcholine in the cerebral cortex is 10-12 seconds. Also, the system expressed acetylcholine at normal levels after 20 minutes following 100 seconds of 60Hz stimulation (6000 total pulses). Based on these observations, each second of 60 Hz stimulation of the basal forebrain requires 12 seconds of recovery time. CONCLUSIONS: These data are foundational for future explorations in developing treatments for pathology involving cholinergic exchange and recycling, with implications in optimizing deep brain stimulation and tailoring pharmaceuticals that augment acetylcholine reuptake. These data also suggest that high-frequency stimulation decreases neurotransmitter output through depletion. Additional experimentation in the future will incorporate acetylcholinesterase inhibitors and additional stimulation patterns to assess clinical response.

Sex‐specific impact of brain estrogen deficiency on astrocyte reactivity, neurodegeneration, and memory loss in aromatase knockout mouse models

AbstractBackgroundNearly two‐thirds of Americans with Alzheimer’s disease (AD) are women, however, the molecular mechanisms underlying this sex difference in AD vulnerability remain unclear. Prior research has reported that women with AD have lower brain estrogen. Yet, how estrogen deficiency modulates this sex difference in AD is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, with high levels in the hippocampus. To explore the underlying mechanism of estrogen deficiency in sex‐specific AD vulnerability, we generated mouse models with brain‐specific aromatase knockout (bArKO) and whole‐body total aromatase knockout (tArKO).MethodWe performed a series of memory and behavior tests including spontaneous alternation, social interaction, and tail suspension tests on 6‐ and 19‐month‐old bArKO and tArKO mice with both sexes (n = 10/group). Hippocampus tissues from these mice (n = 3∼4) were collected for bulk RNA‐seq and qPCR. Brain tissues (n = 5) were fixed and stained for astrocytes and neurons by immunofluorescence. Serum and tissue estrogen were measured using liquid chromatography‐mass spectrometry.ResultAromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairments of spatial working memory and social interaction behavior were found in 19‐month‐old female bArKO and tArKO mice. Female tArKO mice also displayed depression‐like behavior at 6‐ and 19‐month‐old. The number of neurons in the CA1 region was significantly decreased in 19‐month‐old female (but not male) tArKO mice. Bulk RNA‐seq showed abnormal expression of genes associated with astrocyte reactivity (e.g., Gfap, Ctgf, Apoe, Lcn2, Sparc, Bdnf, Col1a1, Col1a2) only in aged female bArKO mice. Given growing evidence indicating a causal relationship between neurotoxic reactive astrocytes and neurodegeneration, this finding indicates brain estrogen deficiency triggering neurotoxic astrocyte reactivity in the hippocampus of aged female bArKO mice.ConclusionOur findings provide novel mechanisms that link estrogen deficiency to sex‐specific astrocyte reactivity in the hippocampus, and neurodegeneration and memory loss in aged female mice. Future studies will focus on defining impact of estrogen signaling deficiency on AD mouse models and identifying druggable targets to inform the development of new therapeutic strategies for the prevention and treatment of AD.

The Influence of Probiotic Supplementation on the Obesity Indexes, Neuroinflammatory and Oxidative Stress Markers, Gut Microbial Diversity, and Working Memory in Obese Thai Children.

Obesity is a worldwide health problem with a complex interaction between gut microbiota and cognition. Several studies have demonstrated that probiotic treatments improve characteristics linked to obesity. The present study aimed to evaluate the effects of probiotic supplementation on the obesity indexes, inflammatory and oxidative stress markers, gut microbiota, and working memory in obese children. Ten obese children were assigned to receive the probiotics (8 × 109 CFU of Lactobacillus paracasei HII01 and Bifidobacterium animalis subsp. lactis) for 12 weeks. Demographic data were recorded. Urine and fecal samples were collected to evaluate biomarkers related to obesity and cognition. Behavioral working memory was assessed using the visual n-back test. Electroencephalography was employed to measure electrical activity during the visual n-back test. All parameters were evaluated at the baseline and after 12 weeks. The results revealed that probiotic supplementation significantly altered some gut microbial metabolites, gut microbiota, total antioxidant capacity, and neuroinflammatory markers. However, no significant changes were observed in the visual n-back test or electroencephalographic recordings after 12 weeks. In conclusion, the use of probiotics might be an alternative treatment that could improve the gut microbial ecosystem and microbial metabolites, as well as host antioxidant and neuroinflammation levels. The preliminary results indicated that further detailed prolonged studies are needed in order to determine the beneficial effects of the studied probiotics.

Gynecological surgery in adulthood imparts cognitive and brain changes in rats: A focus on hysterectomy at short-, moderate-, and long-term intervals after surgery

Premenopausal hysterectomy is associated with a greater relative risk of dementia. We previously demonstrated cognitive impairments in adult rats six weeks after hysterectomy with ovarian conservation compared with intact sham-controls and other gynecological surgery variations. Here, we investigated whether hysterectomy-induced cognitive impairments are transient or persistent. Adult rats received sham-control, ovariectomy (Ovx), hysterectomy, or Ovx-hysterectomy surgery. Spatial working memory, reference memory, and anxiety-like behavior were tested either six-weeks post-surgery, in adulthood; seven-months post-surgery, in early middle-age; or twelve-months post-surgery, in late middle-age. Hysterectomy in adulthood yielded spatial working memory deficits at short-, moderate-, and long-term post-surgery intervals. Serum hormone levels did not differ between ovary-intact, but differed from Ovx, groups. Hysterectomy had no significant impact on healthy ovarian follicle or corpora lutea counts for any post-surgery timepoint compared with intact sham-controls. Frontal cortex, dorsal hippocampus, and entorhinal cortex were assessed for activity-dependent markers. In entorhinal cortex, there were alterations in FOSB and ΔFOSB expression during the early middle-age timepoint, and phosphorylated ERK1/2 levels at the adult timepoint. Collectively, results suggest a primary role for the uterus in regulating cognition, and that memory-related neural pathways may be modified following gynecological surgery. This is the first preclinical report of long-term effects of hysterectomy with and without ovarian conservation on cognition, endocrine, ovarian, and brain assessments, initiating a comprehensive framework of gynecological surgery effects. Translationally, findings underscore critical needs to decipher how gynecological surgeries, especially those involving the uterus, impact the brain and its functions, the ovaries, and overall aging from a systems perspective.

Single-neuron and population measures of neuronal activity in working memory tasks.

Information represented in working memory is reflected in the firing rate of neurons in the prefrontal cortex and brain areas connected to it. In recent years, there has been an increased realization that population measures capture more accurately neural correlates of cognitive functions. We examined how single neuron firing in the prefrontal and posterior parietal cortex of two male monkeys compared with population measures in spatial working memory tasks. Persistent activity was observed in the dorsolateral prefrontal and posterior parietal cortex and firing rate predicted working memory behavior, particularly in the prefrontal cortex. These findings had equivalents in population measures, including trajectories in state space that became less separated in error trials. We additionally observed rotations of stimulus representations in the neuronal state space for different task conditions, which were not obvious in firing rate measures. These results suggest that population measures provide a richer view of how neuronal activity is associated with behavior, largely confirming that persistent activity is the core phenomenon that maintains visual-spatial information in working memory.NEW & NOTEWORTHY Recordings from large numbers of neurons led to a reevaluation of neural correlates of cognitive functions, which traditionally were defined based on responses of single neurons or averages of firing rates. Analysis of neuronal recordings from the dorsolateral prefrontal and posterior parietal cortex revealed that properties of neuronal firing captured in classical studies of persistent activity can account for population representations, though some population characteristics did not have clear correlates in single neuron activity.

Evaluations of memory, anxiety, and the growth factor IGF-1R after post-surgical menopause treatment with a highly selective progestin

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.

Neuronal and astrocytic CB1R signaling differentially modulates goal-directed behavior and working memory by distinct temporal mechanisms.

Several cognitive processes, including instrumental behavior and working memory, are controlled by endocannabinoids acting on cannabinoid receptor 1 (CB1R) in the brain through retrograde and presynaptic inhibition of GABA or glutamate release. However, the temporal mechanisms underlying the control of these cognitive processes by CB1Rs remain largely unknown. Here, we have developed a light-sensitive CB1R chimera (optoCB1R) by replacing the intracellular domains of bovine rhodopsin with those of human CB1R. We demonstrated that light stimulation of optoCB1R triggered canonical CB1R signaling by inhibiting cAMP (but not cGMP or IP1) signaling and activating the MAPK pathway in vitro or in vivo. Moreover, light stimulation of optoCB1R in corticostriatal glutamatergic neurons could temporally inhibit excitatory postsynaptic currents (EPSCs) at the level of seconds. Importantly, transient (3 s) and "time-locked", but not random, activation of optoCB1R signaling in corticostriatal neurons at the time of reward affected animal sensitivity to outcome devaluation and inhibited goal-directed behavior. However, prolonged (~30 min) but not transient (10 or 30 s) activation of astrocytic CB1R signaling in the hippocampus impaired working memory. Consequently, neuronal and astrocytic CB1R signaling differentially regulate working memory and goal-directed behavior through distinct temporal and cellular mechanisms. Ultimately, the pharmacological blockade of adenosine A2AR improved the neuronal and astrocytic CB1R-induced impairments in goal-directed behavior and working memory, possibly through modulation of EPSCs and c-Fos, respectively. Therefore, A2AR may represent a promising target for managing cognitive dysfunction resulting from the use of CB1R drugs.

Intermittent stimulation of the nucleus basalis of Meynert in senile Macaque monkeys improves working memory behavior

Intermittent stimulation of the nucleus basalis of Meynert in senile Macaque monkeys improves working memory behavior

Minocycline Ameliorated LPS-Induced Learning and Memory Impairment by Inhibiting Microglia and Astrocytes Activation in The Hippocampus

INTRODUCTION: Many studies support the notion that neuroinflammation involving glial cells may be the fundamental pathogenic event that lead to brain damage and degeneration in Alzheimer’s disease (AD). The effects of minocycline on glial cells activation in the lipopolysaccharide (LPS) rat model is studied here. MATERIALS AND METHODS: Fifty adult male Sprague Dawley rats were split into five groups: control, LPS, LPS-treated with minocycline 25 mg/kg, LPS-treated with minocycline 50 mg/kg, and LPS treated with memantine 10 mg/kg. For two weeks, rats were treated with minocycline and memantine intraperitoneally daily, while were injected with LPS intraperitoneally once on day 5. Morris water maze (MWM) test was performed to evaluate the learning and working memory behaviour. Immunohistochemistry and Western blot were performed to measure ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expressions in the hippocampal tissue. RESULTS: LPS injection caused significant learning and working memory deficits (p<0.05) as well as increased expressions of Iba-1 and GFAP (p<0.05), indicating microglia and astrocytes activation, respectively. Minocycline treatment significantly improved learning and working memory performance (p<0.05) and reduced microglia/astrocytes activation (p<0.05) in a dose-dependent manner, similar to the effect of memantine. CONCLUSIONS: Our results suggest that minocycline modulates LPS-induced microglia and astrocytes activation as well as improves learning and working memory comparable to memantine. Thus, minocycline may have preventive-therapeutic effect in diseases involving neuroinflammation such as AD.

Working memory training in children with borderline intellectual functioning and neuropsychiatric disorders: a triple-blind randomised controlled trial.

BackgroundPoor working memory, lower IQ and maladaptive behaviour form a triple disability known to have negative effects on the academic and social development of children with borderline intellectual functioning (BIF; IQ: 70 < IQ < 85) and neuropsychiatric disorders [attention‐deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD)]. Treatment possibilities for these children are scarce and hardly evidence based. This study primarily investigated whether adaptive computerised working memory training (WMT) may lead to significantly more improvement on a non‐trained visuospatial WM task compared with a non‐adaptive control WMT (placebo) in children with BIF and neuropsychiatric disorders. As secondary outcome measures, we used the scores on several non‐trained neuropsychological near‐transfer and far‐transfer tasks as well as behavioural measures.MethodWe conducted a triple‐blind placebo‐controlled randomised clinical trial in 72 children (aged 10;0–13;11 years, 53 boys, 19 girls) with BIF and comorbid neuropsychiatric disorders (ADHD = 37, ASD = 21, both = 14) that were referred to child and adolescent psychiatry care, between May 2012 and March 2019. Children completed the Dutch version of Cogmed WMT, either the adaptive training version or the non‐adaptive placebo version, 25 sessions (30–45 min a day), for 5 weeks. The primary outcome measure was the score on a non‐trained visuospatial working memory task. The primary outcome was measured before and directly after 5 weeks of WMT and again 6 months after training.ResultsA total of 375 children were screened for eligibility and 72 were randomised. No significantly higher levels of improvement over time were found on our primary outcome measure in the experimental WMT group compared with the placebo control WMT, nor in the secondary (near‐transfer and far‐transfer tasks) or tertiary (behavioural measures) outcome measures. However, this study did show changes over time for these measurements for both the experimental and placebo conditions.ConclusionsThis study was unable to document superior training effects over time of an adaptive WMT in children with BIF and neuropsychiatric disorders, compared with a placebo (non‐adaptive) WMT. The objectively documented changes over time in the non‐adaptive WMT arm suggest that these children with persistent impairments in WM may benefit from a structured learning environment that is associated with improvement of neurocognitive functioning and coping strategies. Further research is needed to examine which elements of cognitive training may be useful for which specific patients and to study long‐term effects of training.

Curcumin Ameliorates the Cd-Induced Anxiety-like Behavior in Mice by Regulating Oxidative Stress and Neuro-Inflammatory Proteins in the Prefrontal Cortex Region of the Brain.

Age-related neurodegenerative diseases and vascular dementia are major challenges to the modern health care system. Most neurodegenerative diseases are associated with impaired spatial working memory and anxiety-like behavior. Thus, it is important to understand the underlying cellular mechanisms of neurodegenerative diseases in different regions of the brain to develop an effective therapeutic approach. In our previous research paper, we have reported the ameliorative effect of curcumin in Cd-induced hippocampal neurodegeneration. However, recently many researchers had reported the important role of the prefrontal cortex in higher cognitive functions. Therefore, to look into the cellular mechanism of curcumin protection against Cd-induced prefrontal cortex neurotoxicity, we investigated spatial working memory, anxiety-like behavior and analyzed prefrontal cortex inflammatory markers (IL-6, IL-10, and TNFα), antioxidant enzymes (SOD, GSH, and CAT), and pro-oxidant MDA level. Further, we conducted histological studies of the prefrontal cortex in Swiss albino mice exposed to cadmium (2.5 mg/kg). We observed that curcumin treatment improved the spatial working memory and anxiety-like behavior of mice through reduction of prefrontal cortex neuroinflammation and oxidative stress as well as increasing the number of viable prefrontal cortex neuronal cells. Our result suggests that environmental heavy metal cadmium can induce behavioral impairment in mice through prefrontal cortex cellular inflammation and oxidative stress. We found that curcumin has a potential therapeutic property to mitigate these behavioral and biochemical impairments induced by cadmium.

Examining Distinctive Working Memory Profiles in Chinese Children With Predominantly Inattentive Subtype of Attention-Deficit/Hyperactivity Disorder and/or Reading Difficulties

Although evidence has shown that both RD and ADHD-I children suffer from working memory problems, inconsistencies in impaired modalities have been reported. This study aimed to (1) compare the three WM domains (i.e., verbal WM, visual-spatial WM, and behavioral WM) among pure ADHD-I, pure RD, comorbid ADHD-I+RD, and typical control groups and (2) examine the impact of comorbidity on the three WM domains. A Chinese sample of participants from Hong Kong included 29 children in the ADHD-I group, 78 children in the RD group, 31 children in the comorbid group (ADHD-I+RD), and 64 children in the TD control group. All participants completed the assessments individually. The findings showed that the children with ADHD-I and/or RD exhibited diverse cognitive profiles. In particular, RD was associated with verbal and visual-spatial working memory deficits, while ADHD-I was associated with behavioral working memory deficits. Interestingly, the comorbid condition demonstrated additive deficits of the two disorders but with greater deficits in behavioral working memory. These findings support the cognitive subtype hypothesis and provide a clearer picture of the distinctive working memory profiles of different groups, allowing for the development of intervention programs in the future.

Olive leaf extract prevents obesity, cognitive decline, and depression and improves exercise capacity in mice

Obesity is a risk factor for development of metabolic diseases and cognitive decline; therefore, obesity prevention is of paramount importance. Neuronal mitochondrial dysfunction induced by oxidative stress is an important mechanism underlying cognitive decline. Olive leaf extract contains large amounts of oleanolic acid, a transmembrane G protein-coupled receptor 5 (TGR5) agonist, and oleuropein, an antioxidant. Activation of TGR5 results in enhanced mitochondrial biogenesis, which suggests that olive leaf extract may help prevent cognitive decline through its mitochondrial and antioxidant effects. Therefore, we investigated olive leaf extract’s effects on obesity, cognitive decline, depression, and endurance exercise capacity in a mouse model. In physically inactive mice fed a high-fat diet, olive leaf extract administration suppressed increases in fat mass and body weight and prevented cognitive declines, specifically decreased working memory and depressive behaviors. Additionally, olive leaf extract increased endurance exercise capacity under atmospheric and hypoxic conditions. Our study suggests that these promising effects may be related to oleanolic acid’s improvement of mitochondrial function and oleuropein’s increase of antioxidant capacity.

Hippocampal cellular changes in androgen deprived insulin resistant rats.

Androgen deprivation can be achieved through testosterone antagonists (chemical castration) with or without orchidectomy. We use a rat model to characterize hippocampal structural and functional changes that might be associated with a subset population of androgen deprived insulin-resistant patients. Adult male Wistar rats assigned into six (6) groups: control group (distilled water/sham), orchiectomy group (bilateral orchiectomy), flutamide group (oral flutamide; 11mg/kg body weight), diabetes group (multiple low-dose of streptozotocin (STZ; 30mg/kg body weight intraperitoneally), orchiectomy and diabetic group (bilateral orchiectomy with 30mg/kg body weight of STZ), and orchiectomy/diabetic/flutamide group (bilateral orchiectomy with 30mg/kg body weight of STZ with 11mg/kg body weight of flutamide). Animals were sacrificed at 30 and 60days respectively. Spatial learning and working memory behavior were assessed; while total plasma; testosterone, insulin levels, and fasting blood glucose were assayed; the Homeostasis model for insulin resistance was also calculated. Histological examinations by H&E and CFV, while immunohistochemical analysis of astrocytes, P53 protein, and NSE were performed. Androgen deprived insulin-resistant state caused altered learning and cognitive behavior through decreased percentage correct alternation to an increased escape latency period. Significant bidirectional correlates exist between the hormonal profiles relative to the control group (p < 0.05), especially in the 60days post-orchiectomy. While histological and immunohistochemical data indicate microcellular derangement. That the summate effects of androgen deprivation and impaired insulin signaling exacerbate hippocampal neurodegenerative changes that merit further studies.

Ibotenic acid induced lesions impair the modulation of dendritic spine plasticity in the prefrontal cortex and amygdala, a phenomenon that underlies working memory and social behavior

The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.

M1 receptors interacting with NMDAR enhance delay-related neuronal firing and improve working memory performance.

The recurrent excitatory circuits in dlPFC underlying working memory are known to require activation of glutamatergic NMDA receptors (NMDAR). The neurons in these circuits also rely on acetylcholine to maintain persistent activity, with evidence for actions at both nicotinic α7 receptors and muscarinic M1 receptors (M1R). It is known that nicotinic α7 receptors interact with NMDAR in these circuits, but the interactions between M1R and NMDAR on dlPFC neuronal activity are unknown. Here, we investigated whether M1Rs contribute to the permissive effects of ACh in dlPFC circuitry underlying working memory via interactions with NMDA receptors. We tested interactions between M1Rs and NMDARs in vivo on single neuron activity in rhesus macaques performing a working memory task, as well as on working memory behavior in rodents following infusion of M1R and NMDAR compounds into mPFC. We report that M1R antagonists block the enhancing effects of NMDA application, consistent with M1R permissive actions. Conversely, M1R positive allosteric modulators prevented the detrimental effects of NMDAR blockade in single neurons in dlPFC and on working memory performance in rodents. These data support an interaction between M1R and NMDARs in working memory circuitry in both primates and rats, and suggest M1Rs contribute to the permissive actions of ACh in primate dlPFC. These results are consistent with recent data suggesting that M1R agonists may be helpful in the treatment of schizophrenia, a cognitive disorder associated with NMDAR dysfunction.