Melatonin improves maternal sleep deprivation-induced learning and memory impairment, inflammation, and synaptic dysfunction in murine male adult offspring.

INTRODUCTION: Maternal sleep deprivation (MSD), which induces inflammation and synaptic dysfunction in the hippocampus, has been associated with learning and memory impairment in offspring. Melatonin (Mel) has been shown to have anti-inflammatory, antioxidant, and neuroprotective function. However, the beneficial effect of Mel on MSD-induced cognitive impairment and its mechanisms are unknown. METHODS: In the present study, adult offspring suffered from MSD were injected with Mel (20 mg/kg) once a day during postnatal days 61-88. The cognitive function was evaluated by the Morris water maze test. Levels of proinflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mRNA and protein levels of synaptic plasticity associated proteins were examined using reverse transcription-polymerase chain reaction and western blotting. RESULTS: The results showed that MSD impaired learning and memory in the offspring mice. MSD increased the levels of interleukin (IL)-1creIL-6, and tumor necrosis factor-α and decreased the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin in the hippocampus. Furthermore, Mel attenuated cognitive impairment and restored markers of inflammation and synaptic plasticity to control levels. CONCLUSIONS: These findings indicated that Mel could ameliorate learning and memory impairment induced by MSD, and these beneficial effects were related to improvement in inflammation and synaptic dysfunction.

Verbal memory network mapping in individual patients predicts postoperative functional impairments.

Verbal memory decline is a significant concern following temporal lobe surgeries in patients with epilepsy, emphasizing the need for precision presurgical verbal memory mapping to optimize functional outcomes. However, the inter-individual variability in functional networks and brain function-structural dissociations pose challenges when relying solely on group-level atlases or anatomical landmarks for surgical guidance. Here, we aimed to develop and validate a personalized functional mapping technique for verbal memory using precision resting-state functional MRI (rs-fMRI) and neurosurgery. A total of 38 patients with refractory epilepsy scheduled for surgical interventions were enrolled and 28 patients were analyzed in the study. Baseline 30-min rs-fMRI scanning, verbal memory and language assessments were collected for each patient before surgery. Personalized verbal memory networks (PVMN) were delineated based on preoperative rs-fMRI data for each patient. The accuracy of PVMN was assessed by comparing post-operative functional impairments and the overlapping extent between PVMN and surgical lesions. A total of 14 out of 28 patients experienced clinically meaningful declines in verbal memory after surgery. The personalized network and the group-level atlas exhibited 100% and 75.0% accuracy in predicting postoperative verbal memory declines, respectively. Moreover, six patients with extra-temporal lesions that overlapped with PVMN showed selective impairments in verbal memory. Furthermore, the lesioned ratio of the personalized network rather than the group-level atlas was significantly correlated with postoperative declines in verbal memory (personalized networks: r = -0.39, p = .038; group-level atlas: r = -0.19, p = .332). In conclusion, our personalized functional mapping technique, using precision rs-fMRI, offers valuable insights into individual variability in the verbal memory network and holds promise in precision verbal memory network mapping in individuals.

Tactile memory impairments in younger and older adults.

Human tactile memory allows us to remember and retrieve the multitude of somatosensory experiences we undergo in everyday life. An unsolved question is how tactile memory mechanisms change with increasing age. We here use the ability to remember fine-grained tactile patterns passively presented to the fingertip to investigate age-related changes in tactile memory performance. In experiment 1, we varied the degree of similarity between one learned and several new tactile patterns to test on age-related changes in the "uniqueness" of a stored tactile memory trace. In experiment 2, we varied the degree of stimulus completeness of both known and new tactile patterns to test on age-related changes in the weighting between known and novel tactile information. Results reveal that older adults show only weak impairments in both precision and bias of tactile memories, however, they show specific deficits in reaching peak performance > 85% in both experiments. In addition, both younger and older adults show a pattern completion bias for touch, indicating a higher weighting of known compared to new information. These results allow us to develop new models on how younger and older adults store and recall tactile experiences of the past, and how this influences their everyday behavior.

A modified neural circuit framework for semantic memory retrieval with implications for circuit modulation to treat verbal retrieval deficits.

Word finding difficulty is a frequent complaint in older age and disease states, but treatment options are lacking for such verbal retrieval deficits. Better understanding of the neurophysiological and neuroanatomical basis of verbal retrieval function may inform effective interventions. In this article, we review the current evidence of a neural retrieval circuit central to verbal production, including words and semantic memory, that involves the pre-supplementary motor area (pre-SMA), striatum (particularly caudate nucleus), and thalamus. We aim to offer a modified neural circuit framework expanded upon a memory retrieval model proposed in 2013 by Hart et al., as evidence from electrophysiological, functional brain imaging, and noninvasive electrical brain stimulation studies have provided additional pieces of information that converge on a shared neural circuit for retrieval of memory and words. We propose that both the left inferior frontal gyrus and fronto-polar regions should be included in the expanded circuit. All these regions have their respective functional roles during verbal retrieval, such as selection and inhibition during search, initiation and termination of search, maintenance of co-activation across cortical regions, as well as final activation of the retrieved information. We will also highlight the structural connectivity from and to the pre-SMA (e.g., frontal aslant tract and fronto-striatal tract) that facilitates communication between the regions within this circuit. Finally, we will discuss how this circuit and its correlated activity may be affected by disease states and how this circuit may serve as a novel target engagement for neuromodulatory treatment of verbal retrieval deficits.

It's not a lie If you believe it: Narrative analysis of autobiographical memories reveals over-confidence disposition in patients who confabulate.

Humans perceive their personal memories as fundamentally true, and although memory is prone to inaccuracies, flagrant memory errors are rare. Some patients with damage to the ventromedial prefrontal cortex (vmPFC) recall and act upon patently erroneous memories (spontaneous confabulations). Clinical observations suggest these memories carry a strong sense of confidence, a function ascribed to vmPFC in studies of memory and decision making. However, most studies of the underlying mechanisms of memory overconfidence do not directly probe personal recollections and resort instead to laboratory-based tasks and contrived rating scales. We analyzed naturalistic word use of patients with focal vmPFC damage (N = 18) and matched healthy controls (N = 23) while they recalled autobiographical memories using the Linguistic Inquiry and Word Count (LIWC) method. We found that patients with spontaneous confabulation (N = 7) tended to over-use words related to the categories of 'certainty' and of 'swearwords' compared to both non-confabulating vmPFC patients (N = 11) and control participants. Certainty related expressions among confabulating patients were at normal levels during erroneous memories and were over-expressed during accurate memories, contrary to our predictions. We found no elevation in expressions of affect (positive or negative), temporality or drive as would be predicted by some models of confabulation. Thus, erroneous memories may be associated with subjectively lower certainty, but still exceed patients' report criterion because of a global proclivity for overconfidence. This may be compounded by disinhibition reflected by elevated use of swearwords. These findings demonstrate that analysis of naturalistic expressions of memory content can illuminate global meta-mnemonic contributions to memory accuracy complementing indirect laboratory-based correlates of behavior. Memory accuracy is the result of complex interactions among multiple meta-mnemonic processes such as monitoring, report criteria, and control processes which may be shared across decision-making domains.

Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Lower cognitive reserve is related to worse working memory performance in older adults after mTBI. An ERP study.

OBJECTIVE: Older adults (OA) after mild traumatic brain injury (mTBI) have a high risk of developing persistent post-injury cognitive impairments. Lower pre-morbid cognitive reserve (CR) is increasingly investigated as a risk factor for cognitive dysfunction in OA. However, how CR protects against effects of mTBI at the brain level remains largely understudied. METHODS: We examined 22 OA who sustained mTBI (mean 67.69 years, SD 5.11) in the sub-acute phase and 15 age- and CR-matched healthy OA (mean 68 years, SD 5.55) performing a three-level visual N-back task using electroencephalography. We calculated inverse efficiency scores of performance from accuracy and reaction times. Event-related potentials served as neurocognitive correlates of attentional (P2) and working memory (P3) processing. RESULTS: Overall, mTBI OA performed worse than healthy OA (p = 0.031). Lower CR generally decreased performance (p < 0.001). Furthermore, with increasing task difficulty, task performance was more affected by CR (p = 0.004). At the brain level, P2 amplitude was lower in mTBI OA than in healthy OA (p = 0.05). There was no clear effect of CR on P2 or P3 measures. CONCLUSION: As mTBI OA with lower CR performed worse on a working-memory task, lower CR may be a risk factor for worse recovery after mTBI in this group.

Can a failure in the error-monitoring system explain unawareness of memory deficits in Alzheimer's disease?

Unawareness of memory deficits is an early manifestation in patients with Alzheimer's disease (AD), which often delays diagnosis. This intriguing behavior constitutes a form of anosognosia, whose neural mechanisms remain largely unknown. We hypothesized that anosognosia may depend on a critical synaptic failure in the error-monitoring system, which would prevent AD patients from being aware of their own memory impairment. To investigate, we measured event-related potentials (ERPs) evoked by erroneous responses during a word memory recognition task in two groups of amyloid positive individuals with only subjective memory complaints at study entry: those who progressed to AD within the five-year study period (PROG group), and those who remained cognitively normal (CTRL group). A significant reduction in the amplitude of the positivity error (Pe), an ERP related to error awareness, was observed in the PROG group at the time of AD diagnosis (vs study entry) in intra-group analysis, as well as when compared with the CTRL group in inter-group analysis, based on the last EEG acquisition for all subjects. Importantly, at the time of AD diagnosis, the PROG group exhibited clinical signs of anosognosia, overestimating their cognitive abilities, as evidenced by the discrepancy scores obtained from caregiver/informant vs participant reports on the cognitive subscale of the Healthy Aging Brain Care Monitor. To our knowledge, this is the first study to reveal the emergence of a failure in the error-monitoring system during a word memory recognition task at the early stages of AD. This finding, along with the decline of awareness for cognitive impairment observed in the PROG group, strongly suggests that a synaptic dysfunction in the error-monitoring system may be the critical neural mechanism at the origin of unawareness of deficits in AD.

Limbic progesterone receptors regulate spatial memory.

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory is not understood. Male mice expressed PRs, predominately in excitatory neurons, in brain regions that support spatial memory, such as the hippocampus and entorhinal cortex (EC). Furthermore, segesterone, a specific PR agonist, activates neurons in both the EC and hippocampus. We assessed the contribution of PRs in promoting spatial and non-spatial cognitive learning in male mice by examining the performance of mice lacking this receptor (PRKO), in novel object recognition, object placement, Y-maze alternation, and Morris-Water Maze (MWM) tasks. In the recognition test, the PRKO mice preferred the familiar object over the novel object. A similar preference for the familiar object was also seen following the EC-specific deletion of PRs. PRKO mice were also unable to recognize the change in object position. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation and MWM tasks; PR deletion affected animal's performance in both these tasks. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. These studies provide novel insights into the role of PRs in facilitating spatial, declarative memory in males, which may help with finding reproductive partners.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex.

Alzheimer's disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

Mechanistic insight into the role of metformin in Alzheimer's disease.

Alzheimer's disease (AD), a type of dementia, is characterized by progressive memory decline and cognition impairment. Despite the considerable body of evidence regarding AD pathophysiology, current therapies merely slow down the disease progression, and a comprehensive therapeutic approach is unavailable. Accordingly, finding an efficient multifunctional remedy is necessary to blunt the increasing rate of AD incidence in the upcoming years. AD shares pathophysiological similarities (e.g., impairment of cognitive functions, insulin sensitivity, and brain glucose metabolism) with noninsulin-dependent diabetes mellitus (NIDDM), which offers the utilization of metformin, a biguanide hypoglycemic agent, as an alternative therapeutic approach in AD therapy. Emerging evidence has revealed the impact of metformin in patients suffering from AD. It has been described that metformin employs multiple mechanisms to improve cognition and memory impairment in pre-clinical AD models, including reduction of hippocampal amyloid-beta (Aß) plaque and neurofibrillary tangles (NFTs) load, suppression of inflammation, amelioration of mitochondrial dysfunction and oxidative stress, restriction of apoptotic neuronal death, and induction of neurogenesis. This review discusses the pre-clinical evidence, which may shed light on the role of metformin in AD and provide a more comprehensive mechanistic insight for future studies in this area of research.

BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment.

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Aging-related episodic-like memory decline in dogs.

Episodic memory, in humans, is the memory most affected by age-related deterioration or the constitution of neurodegenerative pathologies, such as Alzheimer's disease. However, it is unknown whether this relationship is also present in nonhuman animals. Since studies in birds, rats, primates, and dogs have been shown to have episodic-like memory, more studies aiming to improve the present understanding of this relationship in nonhuman animals are important to aid the development of new translational models for neurodegenerative disorders. Knowing that dogs (Canis familiaris) represent a promising experimental model for neurodegenerative disorders, a memory retrieval test was conducted with 90 clinically healthy domestic dogs of different ages, both sexes, and distinct breeds, for the purpose of evaluating episodic-like memory. The present study adapted a test that corroborates episodic memory requirements through incidental codification of experienced events. We performed a test with two exposure phases, with different characteristics between them, so that in the third phase it was necessary to integrate previous experiences in order to achieve success in the test. In our study, it was possible to verify the decline of episodic memory in elderly dogs, even clinically healthy, regardless of the dogs' sex and size. This episodic-like memory decline observed in elderly dogs may be related to the physiological process of aging or preclinical pathological manifestation of cognitive impairment, similar as reported in humans. More studies should be carried out evaluating episodic-like memory in dogs with suspected of canine cognitive dysfunction syndrome in order to better understand the physiological and pathological behavior of this type of memory in canine species.

Comparing behavior following binge ethanol in adolescent and adult DBA/2 J mice.

The adolescent brain undergoes maturation in areas critically involved in reward, addiction, and memory. Adolescents consume alcohol more than any other drug, typically in a binge-like manner. While adults also binge on alcohol, the adolescent brain is more susceptible to ethanol-related damages due to its ongoing development, which may result in persistent behavioral and physical changes, including differences in myelination in the frontal cortex. Sex also impacts ethanol metabolism and addiction progression, suggesting females are more sensitive than males. This study addressed memory, sociability, ethanol sensitivity, and myelin gene expression changes due to binge ethanol, sex, and age. DBA/2 J males and females were exposed to intermittent binge ethanol (4 g/kg, i.g.) from postnatal day (PND) 29-42 or as adults from PND 64-77. Age groups were tested for behaviors at the early phase (24 h - 7 days) and late phase (starting 3 weeks) after the last dose. Adult prefrontal cortex was collected at both phases. Adolescent ethanol impaired late phase memory while adult ethanol showed no impairment. Meanwhile, adolescent males showed early phase tolerance to ethanol-induced locomotor activation, while adult females showed tolerance at both phases. Adult-treated mice displayed reductions in social interaction. Adult ethanol decreased Mal expression, a gene involved in myelin integrity, at the early phase. No differences in myelin gene expression were observed at the late phase. Thus, adolescent binge ethanol more severely impacts memory and myelin gene expression compared to adult exposure, while adult mice display ethanol-induced reductions in social interaction and tolerance to ethanol's locomotor activation.

Exercise and Syzygium aromaticum reverse memory deficits, apoptosis and mitochondrial dysfunction of the hippocampus in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), the most common disease in the brain, is associated with cognitive and mitochondrial dysfunction. Emerging evidence suggests that endurance training and Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) are effective interventions to maintain oxidative balance and improve cognitive function. AIM OF THE STUDY: The present study aimed to investigate the effect of endurance training and clove oil affect spatial memory, apoptosis, mitochondrial homeostasis, and cognitive function in Alzheimer's rats. MATERIALS AND METHODS: 81 rats were randomly assigned to 9 groups: Healthy (H), sham (sh), Healthy-exercise (HE), Healthy-clove (HC), Healthy-exercise-clove (HEC), Alzheimer's (A), Alzheimer's-exercise (AE), Alzheimer's-clove (AC), and Alzheimer's-exercise-clove (AEC). Alzheimer's induction was induced by the injection of 1-42 amyloid into the CA1 region of the hippocampus. The exercise training protocol was performed for 3 weeks, every day for 30 min in swimming training, and clove oil supplementation (0.1 mg/kg) was gavaged daily for 3 weeks in the supplement rat. Shuttle box test was used to measure spatial memory after the last training session, and to determine the mRNAs and protein levels and apoptosis, Real-Time PCR, immunofluorescent, and tunnel methods were used, respectively. RESULTS: Alzheimer's caused a significant decrease in the PRDX6 and GCN5L1 mRNAs and protein levels and a significant increase in apoptosis in the hippocampus of the Alzheimer's group compared to the control group (P = 0.001). Alzheimer's also reduced the time delay in entering the dark environment and increased the time spent in the dark environment (P = 0.001). Following endurance training and consumption of clove oil, spatial memory (P = 0.001), apoptosis (P = 0.001) and mRNAs and protein levels of PRDX6 (P = 0.001) and GCN5L1 (P = 0.017), were recovered in AE, AC and AEC groups, as compared with A group. CONCLUSION: Swimming training and consumption of clove can possibly be considered as an effective intervention to maintain oxidative balance and improve mitochondrial homeostasis in Alzheimer's disease.

Imbalance Between Prefronto-Thalamic and Sensorimotor-Thalamic Circuitries Associated with Working Memory Deficit in Schizophrenia.

BACKGROUND: Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. METHODS: Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. RESULTS: During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d' score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. CONCLUSIONS: The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function.

Hypothermic preconditioning attenuates hypobaric hypoxia induced spatial memory impairment in rats.

Hypobaric Hypoxia (HH) is known to cause oxidative stress in the brain that leads to spatial memory deficit and neurodegeneration. For decades therapeutic hypothermia is used to treat global and focal ischemia in preserving brain functions that proved to be beneficial in humans and rodents. Considering these previous reports, the present study was designed to establish the therapeutic potential of hypothermia preconditioning on HH induced spatial memory, biochemical and morphological changes in adult rats. Male Sprague Dawley rats were exposed to HH (7620 m, ~ 282 mmHg) for 1, 3 and 7 days with and without hypothermic preconditioning. Spatial learning memory was assessed by Morris water maze (MWM) test along with evaluation of hippocampal pyramidal neuron damage by histological study. Oxidative stress was measured by studying the levels of nitric oxide (NO), reactive oxygen species (ROS), lipid peroxidation (LPO), oxidized and reduced glutathione (GSSG and GSH). Results of MWM test indicated prolonged path length and latency to reach the platform in HH groups that regained to normal in cold pre-treated groups. A likely neurodegeneration was evident in HH groups that lessen in the cold pre-treated groups. Hypothermic preconditioning prevented spatial memory impairment and neurodegeneration in animals subjected to HH via decreasing the NO, ROS and LPO compared to control animals. The GSH level and GSH/GSSG ratio was found to be higher in preconditioned animals as compared to respective HH exposed animals, indicative of redox scavenging and restoration of hippocampal neuronal structure as well as spatial memory. Therefore, hypothermic preconditioning improves spatial memory deficit by reducing HH induced oxidative stress and hippocampal neurodegeneration, hence can be used as a multi-target prophylactic measure to combat HH induced neurodegeneration.