Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Elevations in the Mitochondrial Matrix Protein Cyclophilin D Correlate With Reduced Parvalbumin Expression in the Prefrontal Cortex of Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia. STUDY DESIGN: Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia). STUDY RESULTS: In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter. CONCLUSIONS: Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

Vagus nerve stimulation (VNS) modulates synaptic plasticity in the rat infralimbic cortex via Trk-B receptor activation to reduce drug-seeking.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in rats trained to self-administer cocaine. Pairing 10 days of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay (ELISA). Systemic blockade of Tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Acute Vagus Nerve Stimulation Facilitates Short Term Memory and Cognitive Flexibility in Rats.

Vagus nerve stimulation (VNS) causes the release of several neuromodulators, leading to cortical activation and deactivation. The resulting preparatory cortical plasticity can be used to increase learning and memory in both rats and humans. The effects of VNS on cognition have mostly been studied either in animal models of different pathologies, and/or after extended VNS. Considerably less is known about the effects of acute VNS. Here, we examined the effects of acute VNS on short-term memory and cognitive flexibility in naïve rats, using three cognitive tasks that require comparatively brief (single session) training periods. In all tasks, VNS was delivered immediately before or during the testing phase. We used a rule-shifting task to test cognitive flexibility, a novel object recognition task to measure short-term object memory, and a delayed spontaneous alternation task to measure spatial short-term memory. We also analyzed exploratory behavior in an elevated plus maze to determine the effects of acute VNS on anxiety. Our results indicate that acute VNS can improve memory and cognitive flexibility relative to Sham-stimulation, and these effects are independent of unspecific VNS-induced changes in locomotion or anxiety.

The effects of acamprosate on prefrontal cortical function are mimicked by CaCl2 and they are influenced by the history of alcohol exposure.

Alcohol use disorder is associated with functional changes in the medial prefrontal cortex (mPFC), which include altered glutamatergic transmission and deficits in executive functions that contribute to relapse. Acamprosate (calcium-bis N-acetylhomotaurinate) reduces alcohol craving and relapse, effects that are thought to be mediated by acamprosate's ability to ameliorate alcohol-induced dysregulation of glutamatergic signaling. Treatment with acamprosate and its active moiety calcium (CaCl2) both improve deficits in cognitive flexibility in postdependent mice following chronic intermittent ethanol (CIE) exposure. Here, we show that mice that self-administered alcohol under goal-directed conditions (i.e., operant responding on a fixed-ratio schedule) also display similar deficits in cognitive flexibility and altered glutamatergic signaling in the mPFC, both of which were improved with acamprosate or CaCl2. However, under conditions shown to bias behavior towards habitual responding (operant self-administration after CIE exposure, or on a variable interval schedule), alcohol-induced changes to glutamatergic transmission were unaffected by either acamprosate or CaCl2 treatment. Together, these findings suggest that the variable effects of acamprosate on synaptic signaling may reflect a shift in mPFC networks related to the loss of behavioral control in habitual alcohol-seeking.

Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology.

Synaptic failure underlies cognitive impairment in Alzheimer's disease (AD). Cumulative evidence suggests a strong link between mitochondrial dysfunction and synaptic deficits in AD. We previously found that oligomycin-sensitivity-conferring protein (OSCP) dysfunction produces pronounced neuronal mitochondrial defects in AD brains and a mouse model of AD pathology (5xFAD mice). Here, we prevented OSCP dysfunction by overexpressing OSCP in 5xFAD mouse neurons in vivo (Thy-1 OSCP/5xFAD mice). This approach protected OSCP expression and reduced interaction of amyloid-beta (Aß) with membrane-bound OSCP. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aß-mediated defects in axonal mitochondrial dynamics and motility. Consistent with preserved neuronal mitochondrial function, OSCP overexpression ameliorated synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density, reduced complement-dependent synapse elimination, and improved synaptic transmission, leading to preserved spatial learning and memory. Taken together, our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and implicate OSCP modulation as a potential therapeutic strategy.

Deletion of the Mitochondrial Matrix Protein CyclophilinD Prevents Parvalbumin Interneuron Dysfunctionand Cognitive Deficits in a Mouse Model of NMDA Hypofunction.

Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin (PV)-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory and cognitive processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors (NMDARs) during development [subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11] results in long-lasting alterations in synaptic transmission and reduced PV expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition (NOR). Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.SIGNIFICANCE STATEMENT Mitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor (NMDAR) blockade with ketamine (KET) during development causes oxidative stress, dysfunction of parvalbumin (PV)-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D (CypD) show robust protection from PVI dysfunction following perinatal NMDAR blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.

The Efficacy of Lidocaine in Disrupting Cocaine Cue-Induced Memory Reconsolidation.

RATIONAL: Cue-induced craving memories, linked to drug-seeking behaviors, require key molecular processes for memory reconsolidation. Lidocaine, a sodium channel blocker, inhibits NMDA receptor activation and suppresses nitric oxide and ERK production. These processes are required for memory re-consolidation; inhibiting them may reduce cue-related craving memories in cocaine dependent subjects. OBJECTIVES: To assess the efficacy of lidocaine in decreasing cue-induced cocaine craving and cocaine use. METHODS: Treatment-seeking cocaine-dependent participants (n = 33, 25 men) were recruited. Personalized craving and relaxation scripts were developed. Participants were then randomly assigned in a double-blind design to either receive intravenous lidocaine immediately following a cocaine craving script (lidocaine/craving), saline following a craving script (saline/craving), or lidocaine following a relaxation script (lidocaine/relax). One week following the infusion, cue-induced craving was assessed in the same paradigm without an infusion. Cocaine use and craving were assessed for 4 weeks following infusion. RESULTS: The administration of lidocaine during craving induction (lidocaine/craving) did not decrease cue-induced craving during craving reactivation one week later or craving and cocaine use over the 4-week follow-up period compared to the saline/craving group. There were no significant differences in craving and cocaine use between the lidocaine/relax and saline/craving groups. CONCLUSION: Lidocaine administered following craving induction did not decrease subsequent cue-induced craving or cocaine use. Blocking the reconsolidation of craving-related memories with pharmacological agents remains an important area of investigation.

Near-Infrared Light Triggered-Release in Deep Brain Regions Using Ultra-photosensitive Nanovesicles.

Remote and minimally-invasive modulation of biological systems with light has transformed modern biology and neuroscience. However, light absorption and scattering significantly prevents penetration to deep brain regions. Herein, we describe the use of gold-coated mechanoresponsive nanovesicles, which consist of liposomes made from the artificial phospholipid Rad-PC-Rad as a tool for the delivery of bioactive molecules into brain tissue. Near-infrared picosecond laser pulses activated the gold-coating on the surface of nanovesicles, creating nanomechanical stress and leading to near-complete vesicle cargo release in sub-seconds. Compared to natural phospholipid liposomes, the photo-release was possible at 40 times lower laser energy. This high photosensitivity enables photorelease of molecules down to a depth of 4 mm in mouse brain. This promising tool provides a versatile platform to optically release functional molecules to modulate brain circuits.

Reversal of peripheral nerve injury-induced neuropathic pain and cognitive dysfunction via genetic and tomivosertib targeting of MNK.

Neuropathic pain caused by nerve injury presents with severe spontaneous pain and a variety of comorbidities, including deficits in higher executive functions. None of these clinical problems are adequately treated with current analgesics. Targeting of the mitogen-activated protein kinase-interacting kinase (MNK1/2) and its phosphorylation target, the mRNA cap binding protein eIF4E, attenuates many types of nociceptive plasticity induced by inflammatory mediators and chemotherapeutic drugs but inhibiting this pathway does not alter nerve injury-induced mechanical allodynia. We used genetic manipulations and pharmacology to inhibit MNK-eIF4E activity in animals with spared nerve injury, a model of peripheral nerve injury (PNI)-induced neuropathic pain. We assessed the presence of spontaneous pain using conditioned place preference. We also tested performance in a medial prefrontal cortex (mPFC)-dependent rule-shifting task. WT neuropathic animals showed signs of spontaneous pain and were significantly impaired in the rule-shifting task while genetic and pharmacological inhibition of the MNK-eIF4E signaling axis protected against and reversed spontaneous pain and PNI-mediated cognitive impairment. Additionally, pharmacological and genetic inhibition of MNK-eIF4E signaling completely blocked and reversed maladaptive shortening in the length of axon initial segments (AIS) in the mPFC of PNI mice. Surprisingly, these striking positive outcomes on neuropathic pain occurred in the absence of any effect on mechanical allodynia, a standard test for neuropathic pain efficacy. Our results illustrate new testing paradigms for determining preclinical neuropathic pain efficacy and point to the MNK inhibitor tomivosertib (eFT508) as an important drug candidate for neuropathic pain treatment.

Delay-Period Activity and Executive Functions of the Prefrontal Cortex.

The term "working memory" (WM) describes the ability to maintain and manipulate information in the memory for the guidance of goal-directed behavior.[...].

Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer's disease.

Hippocampal lesions are a defining pathology of Alzheimer's disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in AD have not been fully elucidated. Current therapeutic efforts for AD treatment are not effective in correcting hippocampal synaptic deficits. Growth hormone secretagogue receptor 1α (GHSR1α) is critical for hippocampal synaptic physiology. Here, we report that GHSR1α interaction with ß-amyloid (Aß) suppresses GHSR1α activation, leading to compromised GHSR1α regulation of dopamine receptor D1 (DRD1) in the hippocampus from patients with AD. The simultaneous application of the selective GHSR1α agonist MK0677 with the selective DRD1 agonist SKF81297 rescued Ghsr1α function from Aß inhibition, mitigating hippocampal synaptic injury and improving spatial memory in an AD mouse model. Our data reveal a mechanism of hippocampal vulnerability in AD and suggest that a combined activation of GHSR1α and DRD1 may be a promising approach for treating AD.

Vagus nerve stimulation during extinction learning reduces conditioned place preference and context-induced reinstatement of cocaine seeking.

BACKGROUND: Drug use causes the formation of strong cue/reward associations which persist long after cessation of drug-taking and contribute to the long-term risk of relapse. Extinguishing these associations may reduce cue-induced craving and relapse. Previously, we found that pairing vagus nerve stimulation (VNS) with extinction of cocaine self-administration reduces cue-induced reinstatement; however, it remains unclear whether this was primarily caused by extinguishing the context, the instrumental response, or both. OBJECTIVE: Hypothesis: We hypothesized that VNS can facilitate the extinction of both contextual cues and instrumental responding. METHODS: Extinction of context was first tested using Pavlovian conditioned place preference (CPP). Next, the impact of VNS on the extinction of instrumental responding was assessed under ABA and AAA context conditions. In each extinction context separate groups of rats were either provided the opportunity to perform the instrumental response, or the levers were retracted for the duration of extinction training. Reinstatement was induced by reintroduction of the conditioned stimuli and/or the drug-paired context. Data were analyzed using one-way or two-way repeated measures ANOVAs. RESULTS: VNS during extinction reduced reinstatement of CPP. VNS also reduced cue- and context-induced reinstatement of the instrumental response under both AAA and ABA conditions. The subjects' ability to engage with the lever during extinction was crucial for this effect. P values < 0.05 were considered significant. CONCLUSIONS: Craving occurs in response to a range of conditioned stimuli and contexts; VNS may improve outcomes of behavioral therapy by facilitating extinction of both an instrumental response and/or contextual cues.

Neuropathic Pain Creates an Enduring Prefrontal Cortex Dysfunction Corrected by the Type II Diabetic Drug Metformin But Not by Gabapentin.

Chronic pain patients suffer from pain-related cognitive deficits, even when taking commonly prescribed analgesics. These deficits are likely related to pain-related maladaptive plasticity in the frontal cortex. We sought to model cognitive deficits in mice with neuropathic pain to examine maladaptive morphological plasticity in the mPFC and to assess the effects of several therapeutics. We used an attentional set-shifting task in mice with spared nerve injury (SNI) who received either a single intrathecal injection of an analgesic dose of clonidine, 7 d of 100 mg/kg gabapentin, or 7 d of 200 mg/kg metformin. Male SNI mice were significantly more impaired in the set-shifting task than females. This deficit correlated with a loss of parvalbumin (PV) and reductions in axon initial segment (AIS) length in layers 5/6 of the infralimbic (IL) cortex. Acute pain relief with clonidine had no effect on set-shifting performance, whereas pain relief via 7 day treatment with gabapentin worsened the impairment in both SNI and sham mice. Gabapentin reversed the PV loss in the IL but had no effect on AIS length. Treatment with the AMPK-activator metformin completely reversed the pain-related cognitive impairment and restored AIS length in the IL but had little effect on PV expression. Our findings reveal that neuropathic pain-related cognitive impairments in male mice are correlated to bilateral morphological changes in PV interneurons and layer 5/6 IL pyramidal neuron AIS. Pain relief with metformin can reverse some of the functional and anatomical changes.SIGNIFICANCE STATEMENT Cognitive impairments are a comorbidity of neuropathic pain but are inadequately addressed by existing therapeutics. We used a neuropathic pain model in mice to demonstrate that male (but not female) mice show a robust pain-related deficit in attentional set-shifting, which is associated with structural plasticity in axon initial segments in the infralimbic cortex. These deficits were completely reversed by 7 day treatment with the antidiabetic drug metformin, suggesting that this drug can be repurposed for the treatment of neuropathic pain and its cognitive comorbidities. Our findings have implications for our understanding of how neuropathic pain causes structural plasticity in the brain, and they point to a marked sexual dimorphism in neuropathic pain mechanisms in mice.

Calcium chloride mimics the effects of acamprosate on cognitive deficits in chronic alcohol-exposed mice.

RATIONALE: Acamprosate (calcium-bis N-acetylhomotaurinate) is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Acamprosate can improve executive functions that are impaired by chronic intermittent ethanol (CIE) exposure. Recent work has suggested that acamprosate's effects on relapse prevention are due to its calcium component, which raises the question whether its pro-cognitive effects are similarly mediated by calcium. OBJECTIVES: This study examined the effects of acamprosate on alcohol-induced behavioral deficits and compared them with the effects of the sodium salt version of N-acetylhomotaurinate or calcium chloride, respectively. METHODS: We exposed mice to alcohol via three cycles of CIE and measured changes in alcohol consumption in a limited-access paradigm. We then compared the effects of acamprosate and calcium chloride (applied subchronically for 3 days during withdrawal) in a battery of cognitive tasks that have been shown to be affected by chronic alcohol exposure. RESULTS: CIE-treated animals showed deficits in attentional set-shifting and deficits in novel object recognition. Alcohol-treated animals showed no impairments in social novelty detection and interaction, or delayed spontaneous alternation. Both acamprosate and calcium chloride ameliorated alcohol-induced cognitive deficits to comparable extents. In contrast, the sodium salt version of N-acetylhomotaurinate did not reverse the cognitive deficits. CONCLUSIONS: These results add evidence to the notion that acamprosate produces its anti-relapse effects through its calcium moiety. Our results also suggest that improved regulation of drug intake by acamprosate after withdrawal might at least in part be related to improved cognitive function.

Antioxidant Treatment in Male Mice Prevents Mitochondrial and Synaptic Changes in an NMDA Receptor Dysfunction Model of Schizophrenia.

Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation-inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice. Perinatal treatment with ketamine induced persistent changes in the reduced glutathione/oxidized glutathione (glutathione disulfide) ratio in the medial PFC, indicating long-lasting increases in oxidative stress. Perinatal ketamine treatment also reduced parvalbumin expression, and it induced a decline in mitochondrial membrane potential, as well as elevations in mitochondrial superoxide levels. At the level of synaptic function ketamine reduced inhibition onto layer 2/3 pyramidal cells and increased excitatory drive onto PVI, indicating long-lasting disruptions in the excitation-inhibition balance. These changes were accompanied by layer-specific alterations in NMDAR function in PVIs. All of these changes were mitigated by coadministration of NAC. In addition, NAC given only during late adolescence was also able to restore normal mitochondria function and inhibition at pyramidal cells. These results show that ketamine-induced alterations in PFC physiology correlate with cell type-specific changes in mitochondria function. The ability of NAC to prevent or restore these changes supports the usefulness of antioxidant supplementation in the treatment of schizophrenia.

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment.

Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects.

Increasing the GluN2A/GluN2B Ratio in Neurons of the Mouse Basal and Lateral Amygdala Inhibits the Modification of an Existing Fear Memory Trace.

UNLABELLED: Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone-shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone-shock pairings. To increase the GluN2A/GluN2B ratio after learning, we generated a line of mice that expresses an inducible and doxycycline-dependent GFP-GluN2A transgene specifically in α-CaMKII-positive neurons. Our findings indicate that increasing the GluN2A/GluN2B ratio in BLA α-CaMKII-positive neurons after a weak fear memory has consolidated inhibits retrieval-dependent memory destabilization and modification of the fear memory trace. This was associated with a reduction in retrieval-dependent AMPA receptor trafficking, as evidenced by a reduction in retrieval-dependent phosphorylation of GluR1 at serine-845. In addition, we determined that increasing the GluN2A/GluN2B ratio before fear learning significantly impaired long term memory consolidation, whereas short-term memory remained unaltered. An increase in the GluN2A/GluN2B ratio after fear learning had no influence on fear extinction or expression. Our results underscore the importance of NMDAR subunit composition for memory destabilization and suggest a mechanism for why some memories are resistant to modification. SIGNIFICANCE STATEMENT: Memory modification using reconsolidation updating is being examined as one of the potential treatment approaches for attenuating maladaptive memories associated with emotional disorders. However, studies have shown that, whereas weak memories can be modified using reconsolidation updating, strong memories can be resistant to this approach. Therefore, treatments targeting the reconsolidation process are unlikely to be clinically effective unless methods are devised to enhance retrieval-dependent memory destabilization. Currently, little is known about the cellular and molecular events that influence the induction of reconsolidation updating. Here, we determined that an increase in the GluN2A/GluN2B ratio interferes with retrieval-dependent memory destabilization and inhibits the initiation of reconsolidation updating.

Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease.

F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer's disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aß) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aß disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aß-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.