Long-lasting Cognitive Impairment Research Articles

Detecting and Predicting Cognitive Decline in Individuals with Traumatic Brain Injury: A Longitudinal Telephone-Based Study.

Traumatic brain injuries (TBIs) can lead to long-lasting cognitive impairments, and some survivors experience cognitive decline post-recovery. Early detection of decline is important for care planning, and understanding risk factors for decline can elucidate targets for prevention. While neuropsychological testing is the gold standard approach to characterizing cognitive function, there is a need for brief, scalable tools that are capable of detecting clinically significant changes in post-TBI cognition. This study examines whether a clinically significant change can be detected using the Brief Test of Adult Cognition by Telephone (BTACT) in a sample of individuals with chronic TBI and investigates whether potentially modifiable factors are associated with cognitive decline. Ninety participants aged 40 or older with complicated mild-to-severe TBI participated in two telephone-based study visits ∼1 year apart. Demographic, head trauma exposure, comorbid medical conditions, physical, and psychosocial functioning data were collected via self-report. The BTACT, a brief measure of global cognitive function, was used to assess cognitive performance across six domains. A reliable change index for quantifying clinically significant changes in BTACT performance was calculated. Results revealed cognitive decline in 10-27% of participants across various cognitive domains. More specifically, only depressive symptoms, including depressed affect and anhedonia, were significantly associated with cognitive decline after correcting for multiple comparisons using false discovery rate (FDR). Other factors such as the number of blows to the head, male gender, dyspnea, increased anxiety symptoms, seizures, illicit drug use, and fewer cardiovascular comorbidities should be considered hypothesis generating. Importantly, age was not a significant predictor of cognitive decline, which challenges the assumption that cognitive decline is solely related to the natural aging process. It suggests that there are unique factors associated with TBI that impact cognitive function, and these factors can affect individuals across the lifespan. The BTACT is a brief and sensitive tool for identifying clinically meaningful changes in cognitive function over a relatively brief period (i.e., 1 year) in a sample of individuals in the chronic stages of TBI (i.e., x̄ = 6.7 years post-TBI). Thus, the BTACT may be useful in surveillance efforts aimed at understanding and detecting decline, particularly in situations where in-person cognitive screening is impractical or unfeasible. We also identified potentially modifiable targets for the prevention of post-TBI cognitive decline. These findings can offer insights into treatment goals and preventive strategies for individuals at risk for cognitive decline, as well as help to facilitate early identification efforts.

Inconclusive results of slow cortical potential neurofeedback for the treatment of chronic post-stroke attention deficits.

Individuals who have suffered a stroke may experience long-lasting cognitive impairments that can worsen if left untreated. We investigated whether voluntary control of slow cortical potentials (SCP) through neurofeedback would help alleviate chronic post-stroke symptoms of impaired attention. The study initially enrolled twenty-eight participants, but due to a high drop-out rate, only sixteen participants completed eight SCP neurofeedback training sessions within three to four weeks. During these sessions, we gave feedback to the participants on their ability to regulate SCPs on a computer screen. Our findings showed a non-significant increase in SCP regulation towards cortical negativity. On the behavioral level, we found improved test values in the divided attention and attentional flexibility subtests of the test battery for attention performance. However, we cannot eliminate the possibility that nonspecific effects influenced or caused our results. We have not observed any improvement regarding the effects of attention deficits on participants' daily lives. We identified five individuals who could gain SCP control successfully and consistently towards negativity. In this group of responders, we observed an improvement in the test results related to divided attention but no other attention-related improvements. Based on our observations, results of SCP neurofeedback training for the treatment of attention deficits after a stroke are inconclusive. More research is necessary to determine the effectiveness of SCP neurofeedback in helping stroke survivors cope with attention-related challenges in their daily lives.

The Effects of General Anesthetics on the Developing Brain of Fetus

The Effects of General Anesthetics on the Developing Brain of Fetus

More May Not be Better: Enhanced Spacecraft Shielding May Exacerbate Cognitive Decrements by Increasing Pion Exposures during Deep Space Exploration.

The pervasiveness of deep space radiation remains a confounding factor for the transit of humans through our solar system. Spacecraft shielding both protects astronauts but also contributes to absorbed dose through galactic cosmic ray interactions that produce secondary particles. The resultant biological effects drop to a minimum for aluminum shielding around 20 g/cm2 but increase with additional shielding. The present work evaluates for the first time, the impact of secondary pions on central nervous system functionality. The fractional pion dose emanating from thicker shielded spacecraft regions could contribute up to 10% of the total absorbed radiation dose. New results from the Paul Scherrer Institute have revealed that low dose exposures to 150 MeV positive and negative pions, akin to a Mars mission, result in significant, long-lasting cognitive impairments. These surprising findings emphasize the need to carefully evaluate shielding configurations to optimize safe exposure limits for astronauts during deep space travel.

Anesthetics inhibit phosphorylation of the ribosomal protein S6 in mouse cultured cortical cells and developing brain.

The development and maintenance of neural circuits is highly sensitive to neural activity. General anesthetics have profound effects on neural activity and, as such, there is concern that these agents may alter cellular integrity and interfere with brain wiring, such as when exposure occurs during the vulnerable period of brain development. Under those conditions, exposure to anesthetics in clinical use today causes changes in synaptic strength and number, widespread apoptosis, and long-lasting cognitive impairment in a variety of animal models. Remarkably, most anesthetics produce these effects despite having differing receptor mechanisms of action. We hypothesized that anesthetic agents mediate these effects by inducing a shared signaling pathway. We exposed cultured cortical cells to propofol, etomidate, or dexmedetomidine and assessed the protein levels of dozens of signaling molecules and post-translational modifications using reverse phase protein arrays. To probe the role of neural activity, we performed separate control experiments to alter neural activity with non-anesthetics. Having identified anesthetic-induced changes in vitro, we investigated expression of the target proteins in the cortex of sevoflurane anesthetized postnatal day 7 mice by Western blotting. All the anesthetic agents tested in vitro reduced phosphorylation of the ribosomal protein S6, an important member of the mTOR signaling pathway. We found a comparable decrease in cortical S6 phosphorylation by Western blotting in sevoflurane anesthetized neonatal mice. Using a systems approach, we determined that propofol, etomidate, dexmedetomidine, and APV/TTX all similarly modulate a signaling module that includes pS6 and other cell mediators of the mTOR-signaling pathway. Reduction in S6 phosphorylation and subsequent suppression of the mTOR pathway may be a common and novel signaling event that mediates the impact of general anesthetics on neural circuit development.

Lipopolysaccharide-induced endotoxaemia during adolescence promotes stress vulnerability in adult mice via deregulation of nuclear factor erythroid 2-related factor 2 in the medial prefrontal cortex.

Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear. To determine whether LPS-induced endotoxaemia in adolescence can modulate the stress vulnerability to depressive and anxiety-like behaviours in adulthood and explore the underlying molecular mechanisms. Quantitative real-time PCR was used to measure inflammatory cytokine expression in the brain. A stress vulnerability model was established by exposure to subthreshold social defeat stress (SSDS), and depressive- and anxiety-like behaviours were evaluated by the social interaction test (SIT), sucrose preference test (SPT), tail suspension test (TST), force swimming test (FST), elevated plus-maze (EPM) test, and open field test (OFT). Western blotting was used to measure Nrf2 and BDNF expression levels in the brain. Our results showed that inflammation occurred in the brain 24h after the induction of LPS-induced endotoxaemia at P21 but resolved in adulthood. Furthermore, LPS-induced endotoxaemia during adolescence promoted the inflammatory response and the stress vulnerability after SSDS during adulthood. Notably, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and BDNF in the mPFC were decreased after SSDS exposure in mice treated with LPS during adolescence. Activation of the Nrf2-BDNF signalling pathway by sulforaphane (SFN), an Nrf2 activator, ameliorated the effect of LPS-induced endotoxaemia during adolescence on stress vulnerability after SSDS during adulthood. Our study identified adolescence as a critical period during which LPS-induced endotoxaemia can promote stress vulnerability during adulthood and showed that this effect is mediated by impairment of Nrf2-BDNF signalling in the mPFC.

Astilbin attenuates neonatal postnatal immune activation-induced long-lasting cognitive impairment in adult mice

Postnatal immune activation (PIA) often induces neuroinflammation and disrupts neural functions, ultimately causing cognitive impairment. Among them, neuronal dysfunction is one of the key causes of many neurological diseases. It is particularly important to develop effective neuroprotectants to prevent inflammatory brain diseases. Recently, the protective effect of astilbin (ASB) on nervous system diseases has attracted much attention. However, whether ASB can resolve neuronal dysfunction and cognitive decline triggered by PIA remains unclear. In this study, we used the lipopolysaccharide (LPS)-induced PIA model and found that ASB improved PIA-induced cognitive impairment and neuronal dysfunction in adult mice. Moreover, ASB inhibited PIA-induced neurogenesis deficits and synaptic damage. Finally, we found that ASB treatment inhibited the levels of EZH2/H3K27me3 and decreased the enrichment level of H3K27me3 at the promoter of BCL2 and BDNF. Together, our results demonstrated that ASB may protect against PIA-induced cognitive impairment through EZH2-mediated histone methylation. This study established the role of ASB and epigenetic factor EZH2 regulatory network on the PIA model, which provided new clues and theoretical guidance for the clinical treatment of PIA-induced cognitive impairment.

Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions.

Chronic exposure to Δ-9-tetrahydrocannabinol (THC) during adolescence is associated with long-lasting cognitive impairments and enhanced susceptibility to anxiety and mood disorders. Previous evidence has revealed functional and anatomical dissociations between the posterior vs. anterior portions of the hippocampal formation, which are classified as the dorsal and ventral regions in rodents, respectively. Notably, the dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing. While adolescent THC exposure can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus, it is not currently understood how the dorsal vs. ventral hippocampal regions are affected by THC during neurodevelopment. In the present study, we used an integrative combination of behavioral, molecular, and neural assays in a neurodevelopmental rodent model of adolescent THC exposure. We report that adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions. In addition, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), we show for the first time that adolescent THC exposure induces significant and enduring dysregulation of GABA and glutamate levels in dorsal vs. ventral hippocampus. Finally, adolescent THC exposure induced dissociable dysregulations of hippocampal glutamatergic signaling, characterized by differential glutamatergic receptor expression markers, profound alterations in pyramidal neuronal activity and associated oscillatory patterns in dorsal vs. ventral hippocampal subregions.

Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice.

BackgroundProlonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment.Materials and methodsPostnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot.ResultsOur results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment.ConclusionDisodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.

Pulmonary Endothelial Tau Aggregation After Infection

Patients who recover from nosocomial pneumonia oftentimes exhibit long‐lasting cognitive impairment comparable to what is observed in Alzheimer’s Disease patients. We previously hypothesized that the lung endothelium contributes to infection‐related neurocognitive dysfunction, since bacteria‐exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long‐term potentiation in the hippocampus. However, lung endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection‐induced endothelial cytotoxic tau can trigger neuronal tau aggregation which is the major hallmark of several neuropathologies. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule‐binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, cells were infected with P. aeruginosa. The infection‐induced tau released from endothelium into the medium induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule‐binding repeat domains or the full‐length tau. Infection‐induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial‐derived tau to cause neuronal tau aggregation, was abolished using tau knockout cells. After bacterial lung infection, brain homogenates from wild‐type mice, but not from tau knockout mice, initiated tau aggregation. Notably, plasma samples obtained from pneumonia‐positive patients showed significantly higher tau aggregation activity when compared to pneumonia‐negative plasma samples. Thus, bacterial pneumonia initiates the release of lung endothelial‐derived cytotoxic tau into the circulation, which is capable of propagating a neuronal tauopathy.

Repeated Neonatal Exposure to Sevoflurane Induces Age-Dependent Impairments in Cognition and Synaptic Plasticity in Mice

Background: Sevoflurane is a volatile anesthetic that is widely used in pediatric anesthesia due to its low toxicity. However, whether neonatal exposure to sevoflurane induces long-lasting cognitive impairment remains unclear. It has been reported that neuronal injury is the main cause of sevoflurane-induced learning and memory disabilities in the development of brain. But, the specific mechanism is not well elucidated. The injury of synapse occurs earlier than that of neuronal cell in brain injury. The synaptic plasticity is involved in learning and memory. Methods: We compared the learning and memory ability of neonatal mice to sevoflurane for once or three times in vitro and synaptic plasticity as well as neuronal excitability in vivo. In this study, neonatal C57BL/6J mice were exposed to 3% sevoflurane for 2 h on postnatal day 7 (P7) or once daily for 3 consecutive days (P7/8/9). The Morris water maze test was performed to evaluate the cognitive performance on P31 and P61, respectively. Theta burst stimulation-induced long-term potentiation (LTP) was measured in acute hippocampal slices from P38 and P68 mice to assess the synaptic plasticity. Primary hippocampal neurons were isolated from 24-h-old mice and exposed to different doses of sevoflurane (1, 2, and 3 minimum alveolar anesthetic concentration [MAC]) for 6 h to examine the neuronal excitability. Results: The results showed that compared with the control, repeated exposure to sevoflurane resulted in significant cognitive impairment in adolescent mice, while showing no effect on adult mice. Repeated exposure to sevoflurane remarkably attenuated hippocampal LTP of adolescent mice, which turned to normal in adult mice. No significant difference of LTP was observed between control mice and one-dose sevoflurane-treated mice both in adolescent and adult mice. In primary hippocampal neurons, 2 MAC and 3 MAC sevoflurane delayed neuronal excitation and dose-dependently reduced the number of evoked action potentials compared with control. These effects disappeared after a 24-h recovery. Conclusions: These data suggested that sevoflurane may impair cognitive performance and neuronal plasticity when administered repeatedly or in a high MAC during infancy, which is noticeable during adolescence but alleviates during adulthood.

Association between unmet medication needs after hospital discharge and readmission or death among acute respiratory failure survivors: the addressing post-intensive care syndrome (APICS-01) multicenter prospective cohort study

IntroductionSurvivors of acute respiratory failure (ARF) commonly experience long-lasting physical, cognitive, and/or mental health impairments. Unmet medication needs occurring immediately after hospital discharge may have an important effect on subsequent recovery.Methods and analysisIn this multicenter prospective cohort study, we enrolled ARF survivors who were discharged directly home from their acute care hospitalization. The primary exposure was unmet medication needs. The primary outcome was hospital readmission or death within 3 months after discharge. We performed a propensity score analysis, using inverse probability weighting for the primary exposure, to evaluate the exposure–outcome association, with an a priori sample size of 200 ARF survivors.ResultsWe enrolled 200 ARF survivors, of whom 107 (53%) were female and 77 (39%) were people of color. Median (IQR) age was 55 (43–66) years, APACHE II score 20 (15–26) points, and hospital length of stay 14 (9–21) days. Of the 200 participants, 195 (98%) were in the analytic cohort. One hundred fourteen (57%) patients had at least one unmet medication need; the proportion of medication needs that were unmet was 6% (0–15%). Fifty-six (29%) patients were readmitted or died by 3 months; 10 (5%) died within 3 months. Unmet needs were not associated (risk ratio 1.25; 95% CI 0.75–2.1) with hospital readmission or death, although a higher proportion of unmet needs may have been associated with increased hospital readmission (risk ratio 1.7; 95% CI 0.96–3.1) and decreased mortality (risk ratio 0.13; 95% CI 0.02–0.99).DiscussionUnmet medication needs are common among survivors of acute respiratory failure shortly after discharge home. The association of unmet medication needs with 3-month readmission and mortality is complex and requires additional investigation to inform clinical trials of interventions to reduce unmet medication needs.Study registration number: NCT03738774. The study was prospectively registered before enrollment of the first patient.

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable with what is observed in Alzheimer’s disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, because bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, the full-length lung and endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau triggers neuronal tau aggregation. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule-binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, the cells were infected with Pseudomonas aeruginosa. The infection-induced tau released from endothelium into the medium-induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule-binding repeat domains or the full-length tau. Infection-induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial-derived tau to cause neuronal tau aggregation, was abolished in tau knockout cells. After bacterial lung infection, brain homogenates from WT mice, but not from tau knockout mice, initiated tau aggregation. Thus, we conclude that bacterial pneumonia initiates the release of lung endothelial-derived cytotoxic tau, which is capable of propagating a neuronal tauopathy.

CA3 excitatory synapse loss as a chronic effect of septic shock in middle-aged mice.

Septic encephalopathy represents an acute cerebral dysfunction following systemic inflammation by pathogens. Notably, more than 70% of sepsis survivors present this disorder years after the hospital discharge (Widmann and Heneka, 2014). In rodents, septic shock can be modelled by an intraperitoneal injection of lipopolysaccharide (LPS), and our previous findings indicate that LPS can lead to neuronal loss and synaptic destruction accompanied by glial activation (Semmler et al., 2007; Weberpals et al., 2009; Tejera et al., 2019). However, it remains elusive what ultimately drives this cognitive impairment and how neuroinflammation contributes to these cerebral changes. We intraperitoneally injected 1.5 mg/kg LPS on two consecutive days in mice at 14 months of age. Two different serotypes of LPS (Salmonella enterica and E. coli O55:B5) were compared. The brains were biochemically and histologically analysed at 7 or 63 days post-injection (dpi) in order to study cytokine levels, microglia morphology, neuron/synapse loss and synaptic pruning by microglia. To quantify number of synapses and synaptic pruning, synaptic puncta were visualised by a super-resolution microscope with an Airyscan detector. Proinflammatory responses to septic shock were detected at 7 dpi, including elevated cytokines and the less ramified morphology of microglia. These changes were mostly normalised at 63 dpi, except a persisting high IL-6 level. Neuron density in the hippocampus was found to be normal at 7 dpi and 63 dpi. However, excitatory synapses and synaptic complement factor C3 were reduced in the CA3 at 63 dpi. Similar changes were not obtained at 7 dpi and in other subfields (CA1 and DG). Moreover, the engulfed synaptic puncta density inside CA1 and CA3 microglia lysosomes remained normal at 7 dpi and 63 dpi. Neuroinflammation elicited by systemic LPS injection was mostly resolved at 63 dpi, while the IL-6 level remained elevated. Whereas the hippocampal neurons were intact, the excitatory CA3 synapses were locally reduced by 63 dpi in a manner independent of microglial synaptic pruning. We postulate this synapse loss might be associated with the long-lasting cognitive impairments of sepsis survivors.

Modafinil rescues repeated morphine-induced synaptic and behavioural impairments via activation of D1R-ERK-CREB pathway in medial prefrontal cortex.

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.

Neuron-Glia Crosstalk Plays a Major Role in the Neurotoxic Effects of Ketamine via Extracellular Vesicles.

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

Rapamycin prevents the long-term impairing effects of adolescence Δ-9-tetrahydrocannabinol on memory and plasticity in male rats.

Long-lasting cognitive impairment is one of the most central negative consequences related to the exposure to cannabis during adolescence and particularly of Δ-9-tetrahydrocannabinol (THC). The aim of this study was to compare the protracted effects of adolescent versus late-adolescent chronic exposure to THC on short-term memory and plasticity and to examine whether rapamycin, a blocker of the mammalian target of rapamycin (mTOR) pathway, can restore THC-induced deficits in memory and plasticity. Male rats were injected with ascending doses of THC [2.5, 5, 10mg/kg; intraperitoneally (i.p.)] during adolescence and late-adolescence (post-natal days 30-41 and 45-56, respectively), followed by daily injections of rapamycin (1mg/kg, i.p.) during the first 10 days of cessation from THC. Thirty days after the last injection, rats were tested for short-term and working memory, anxiety-like behaviour, and plasticity in the pathways projecting from the ventral subiculum (vSub) of the hippocampus to the prefrontal cortex (PFC) and nucleus accumbens (NAc). THC exposure in adolescence, but not late-adolescence, was found to induce long-term deficits in object recognition short-term memory and synaptic plasticity in the hippocampal-accumbens pathway. Importantly, rapamycin rescued these persistent effects of THC administered during adolescence. Our findings show that some forms of memory and plasticity are sensitive to chronic THC administration during adolescence and that rapamycin administered during THC cessation may restore cognitive function and plasticity, thus potentially protecting against the possible long-term harmful effects of THC.

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

Pharmacological rescue of cognitive function in a mouse model of chemobrain

BackgroundAfter chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain.MethodMice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot.ResultsMice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor.ConclusionWe establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

ICU Survivorship-The Relationship of Delirium, Sedation, Dementia, and Acquired Weakness.

The advent of modern critical care medicine has revolutionized care of the critically ill patient in the last 50 years. The Society of Critical Care Medicine (was formed in recognition of the challenges and need for specialized treatment for these fragile patients. As the specialty has grown, it has achieved impressive scientific advances that have reduced mortality and saved lives. With those advances, however, came growing recognition that the burden of critical illness did not end at the doorstep of the hospital. Delirium, once thought to be a mere by-product of critical illness, was found to be an independent predictor of mortality, prolonged mechanical ventilation, and long-lasting cognitive impairment. Similarly, deep sedation and immobility, so often used to keep patients "comfortable" and to facilitate mechanical ventilation and recovery, worsen mortality and lead to the development of ICU-acquired weakness. The realization that these outcomes are inextricably linked to one another and how we manage our patients has helped us recognize the need for culture change. We, as a specialty, now understand that although celebrating the successes of survival, we now also have a duty to focus on those who survive their diseases. Led by initiatives such as the ICU Liberation Campaign of the Society of Critical Care Medicine, the natural progression of the field is now focused on getting patients back to their homes and lives unencumbered by disability and impairment. Much work remains to be done, but the futures of our most critically ill patients will continue to benefit if we leverage and build on the history of our first 50 years.