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The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.

Most everyday memories including many episodic-like memories that we may form automatically in the hippocampus (HPC) are forgotten, while some of them are retained for a long time by a memory stabilization process, called initial memory consolidation. Specifically, the retention of everyday memory is enhanced, in humans and animals, when something novel happens shortly before or after the time of encoding. Converging evidence has indicated that dopamine (DA) signaling via D1/D5 receptors in HPC is required for persistence of synaptic plasticity and memory, thereby playing an important role in the novelty-associated memory enhancement. In this review paper, we aim to provide an overview of the key findings related to D1/D5 receptor-dependent persistence of synaptic plasticity and memory in HPC, especially focusing on the emerging evidence for a role of the locus coeruleus (LC) in DA-dependent memory consolidation. We then refer to candidate brain areas and circuits that might be responsible for detection and transmission of the environmental novelty signal and molecular and anatomical evidence for the LC-DA system. We also discuss molecular mechanisms that might mediate the environmental novelty-associated memory enhancement, including plasticity-related proteins that are involved in initial memory consolidation processes in HPC.

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH + ) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH + neurons project more profusely than ventral tegmental area TH + neurons to the hippocampus, optogenetic activation of locus coeruleus TH + neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH + photoactivation are sensitive to hippocampal D 1 /D 5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo . Thus, locus coeruleus TH + neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus. Projections from the locus coeruleus, an area typically defined by noradrenergic signalling, to the hippocampus drive novelty-based memory enhancement through possible co-release of dopamine. Memory consolidation in the locus coeruleus Memory retention can be enhanced when something novel or categorically relevant occurs shortly before or after the time of memory encoding, as in 'flashbulb memory'. Dopamine-based mechanisms originating in the ventral tegmental area have been implicated in the phenomenon. These authors suggest that projections from the locus coeruleus—typically defined by noradrenergic signalling—to the hippocampus drive this novelty-based memory enhancement through the possible local release of dopamine.

The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.

Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients. Graphical abstract

While renal replacement therapy (RRT) allows for precise fluid management as well as addressing electrolyte imbalances and the removal of other necessary compounds, its early initiation has not shown benefit in the general critically ill population. Moreover, the effects of early RRT initiation specifically in patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) also remain unclear. This retrospective study investigated adult patients who underwent VA-ECMO between April 2018 and March 2022 and used the clone-censor-weight method to emulate a hypothetical target trial and compare two groups: patients who initiated RRT within 2 days of VA-ECMO initiation (Early) and those who did not (Late). The primary outcomes were 28-day and 90-day hospital mortality analyzed by Cox proportional hazards models and the secondary outcome was 90-day RRT dependence by pooled logistic regression models. Inverse probability censoring weights were applied to adjust the models. A total of 2,513 VA-ECMO patients were cloned into both groups. The 28-day and 90-day mortalities were lower in the Early group (HR 0.59 [95% CI 0.53–0.68] and 0.67 [0.61–0.75]). However, the early group experienced greater RRT dependence at 90 days than the late group (OR 2.58 [1.94–3.46]). In conclusion, early initiation of RRT (within 2 days of VA-ECMO) was associated with lower hospital mortality but with a higher likelihood of 90-day RRT dependence in adult patients on VA-ECMO.

Background Fluid balance gap (FBgap—prescribed vs. achieved) is associated with hospital mortality. Downtime is an important quality indicator for the delivery of continuous renal replacement therapy (CRRT). We examined the association of CRRT downtime with FBgap and clinical outcomes including mortality. Methods This is a retrospective cohort study of critically ill adults receiving CRRT utilizing both electronic health records (EHR) and CRRT machine data. FBgap was calculated as achieved minus prescribed fluid balance. Downtime, or percent treatment time loss (%TTL), was defined as CRRT downtime in relation to the total CRRT time. Data collection stopped upon transition to intermittent hemodialysis when applicable. Linear and logistic regression models were used to analyze the association of %TTL with FBgap and hospital mortality, respectively. Covariates included demographics, Sequential Organ Failure Assessment (SOFA) score at CRRT initiation, use of organ support devices, and the interaction between %TTL and machine alarms. Results We included 3630 CRRT patient-days from 500 patients with a median age of 59.5 years (IQR 50–67). Patients had a median SOFA score at CRRT initiation of 13 (IQR 10–16). Median %TTL was 8.1% (IQR 4.3–12.5) and median FBgap was 17.4 mL/kg/day (IQR 8.2–30.4). In adjusted models, there was a significant positive relationship between FBgap and %TTL only in the subgroup with higher alarm frequency (6 + alarms per CRRT-day) (β = 0.87 per 1% increase, 95%CI 0.48–1.26). No association was found in the subgroups with lower alarm frequency (0–2 and 3–5 alarms). There was no statistical evidence for an association between %TTL and hospital mortality in the adjusted model with the interaction term of alarm frequency. Conclusions In critically ill adult patients undergoing CRRT, %TTL was associated with FBgap only in the subgroup with higher alarm frequency, but not in the other subgroups with lower alarms. No association between %TTL and mortality was observed. More frequent alarms, possibly indicating unexpected downtime, may suggest compromised CRRT delivery and could negatively impact FBgap.

Background Changes in platelet and white blood cell (WBC) counts during CRRT could identify patients at risk for adverse outcomes. We examined the association of change in platelet and WBC from pre-CRRT to during-CRRT with hospital mortality. Methods This multicenter, retrospective cohort study included 1,413 adults with AKI requiring CRRT at two tertiary medical centers (2011–2021). Platelet and WBC change from pre- to during CRRT were assessed as a percentage and categorized by standard deviation (SD). Multivariable LASSO regression and interaction analyses investigated associations with hospital mortality. Results A > 1 SD platelet count drop during CRRT was independently associated with hospital mortality (aOR: 1.82, 95% CI: 1.06, 3.13). A > 1 SD WBC count increase during CRRT did not significantly increase mortality (aOR 1.41, 95% CI: 0.88, 2.29). Interaction analyses revealed four sub-groups associated with increased mortality: pre-CRRT low platelet count that remained low, pre-CRRT normal platelet count that decreased, pre-CRRT elevated WBC count that remained high, and normal or elevated pre-CRRT WBC count that increased. Interpretation In critically ill adults, a drop in platelets after CRRT initiation was associated with increased hospital mortality. Monitoring platelet and WBC during CRRT in reference to pre-CRRT levels could help identify high-risk patients.

Dopamine (DA) and norepinephrine (NE) are pivotal neuromodulators that regulate a broad range of brain functions, often in concert. Despite their physiological importance, untangling the relationship between DA and NE in the fine control of output function is currently challenging, primarily due to a lack of techniques to allow the observation of spatiotemporal dynamics with sufficiently high selectivity. Although genetically encoded fluorescent biosensors have been developed to detect DA, their poor selectivity prevents distinguishing DA from NE. Here, we report the development of a red fluorescent genetically encoded GPCR (G protein-coupled receptor)-activation reporter for DA termed ‘R-GenGAR-DA’. More specifically, a circular permutated red fluorescent protein (cpmApple) was replaced by the third intracellular loop of human DA receptor D1 (DRD1) followed by the screening of mutants within the linkers between DRD1 and cpmApple. We developed two variants: R-GenGAR-DA1.1, which brightened following DA stimulation, and R-GenGAR-DA1.2, which dimmed. R-GenGAR-DA1.2 demonstrated a reasonable dynamic range ( ΔF/F 0  = − 43%), DA affinity (EC 50  = 0.92 µM) and high selectivity for DA over NE (66-fold) in HeLa cells. Taking advantage of the high selectivity of R-GenGAR-DA1.2, we monitored DA in presence of NE using dual-color fluorescence live imaging, combined with the green-NE biosensor GRAB NE1m , which has high selectivity for NE over DA (> 350-fold) in HeLa cells and hippocampal neurons grown from primary culture. Thus, this is a first step toward the multiplex imaging of these neurotransmitters in, for example, freely moving animals, which will provide new opportunities to advance our understanding of the high spatiotemporal dynamics of DA and NE in normal and abnormal brain function.

Alterations in long-range functional connectivity between distinct brain regions are thought to contribute to the encoding of memory. However, little is known about how the activation of an existing network of neocortical and hippocampal regions might support the assimilation of relevant new information into the preexisting knowledge structure or ‘schema’. Using functional mapping for expression of plasticity-related immediate early gene products, we sought to identify the long-range functional network of paired-associate memory, and the encoding and assimilation of relevant new paired-associates. Correlational and clustering analyses for expression of immediate early gene products revealed that midline neocortical-hippocampal connectivity is strongly associated with successful memory encoding of new paired-associates against the backdrop of the schema, compared to both (1) unsuccessful memory encoding of new paired-associates that are not relevant to the schema, and (2) the mere retrieval of the previously learned schema. These findings suggest that the certain midline neocortical and hippocampal networks support the assimilation of newly encoded associative memories into a relevant schema.