Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin.

Layer 3 (L3) pyramidal neurons in aged rhesus monkey lateral prefrontal cortex (LPFC) exhibit significantly elevated excitability in vitro and reduced spine density compared to neurons in young subjects. The time-course of these alterations, and whether they can be ameliorated in middle age by the powerful anti-oxidant curcumin is unknown. We compared the properties of L3 pyramidal neurons from the LPFC of behaviorally characterized rhesus monkeys over the adult lifespan using whole-cell patch clamp recordings and neuronal reconstructions. Working memory (WM) impairment, neuronal hyperexcitability, and spine loss began in middle age. There was no significant relationship between neuronal properties and WM performance. Middle-aged subjects given curcumin exhibited better WM performance and less neuronal excitability compared to control subjects. These findings suggest that the appropriate time frame for intervention for age-related cognitive changes is early middle age, and points to the efficacy of curcumin in delaying WM decline. Because there was no relationship between excitability and behavior, the effects of curcumin on these measures appear to be independent.

Cordycepin suppresses glutamatergic and GABAergic synaptic transmission through activation of A1 adenosine receptor in rat hippocampal CA1 pyramidal neurons.

Cordycepin (known as 3-deoxyadenosine, CRD), a natural product from the valuable traditional Chinese medicine Cordyceps militaris, has been reported to improve cognitive function and modulate neuroprotective effects on the central nervous system (CNS). However, the modulating mechanisms of cordycepin on information processing in hippocampal CA1 pyramidal neurons are not fully understood. To clarify how cordycepin modulates synaptic responses of pyramidal neurons in rat hippocampal CA1 region, we conducted an electrophysiological experiment using whole-cell patch-clamp technique. The spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) and the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) recorded by this technique evaluated pure single or multi-synapse responses and enabled us to accurately quantify how cordycepin influenced the pre and postsynaptic aspects of synaptic transmission. The present results showed that cordycepin significantly decreased the frequency of both glutamatergic and GABAergic postsynaptic currents without affecting the amplitude, while these inhibitory effects were antagonized by the A1 adenosine receptor antagonist (DPCPX), but not the A2A (ZM 241385), A2B (MRS1754) and A3 (MRS1191) adenosine receptor antagonists. Taken together, our results suggested that cordycepin had a clear presynaptic effect on glutamatergic and GABAergic transmission, and provided novel evidence that cordycepin suppresses the synaptic transmission through the activation of A1AR.

Neuroprotective and Anti-Inflammatory Effects of Pinus densiflora Bark Extract in Gerbil Hippocampus Following Transient Forebrain Ischemia.

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down's syndrome mouse model.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

Lithium Enhances the GABAergic Synaptic Activities on the Hypothalamic Preoptic Area (hPOA) Neurons.

Lithium (Li+) salt is widely used as a therapeutic agent for treating neurological and psychiatric disorders. Despite its therapeutic effects on neurological and psychiatric disorders, it can also disturb the neuroendocrine axis in patients under lithium therapy. The hypothalamic area contains GABAergic and glutamatergic neurons and their receptors, which regulate various hypothalamic functions such as the release of neurohormones, control circadian activities. At the neuronal level, several neurotransmitter systems are modulated by lithium exposure. However, the effect of Li+ on hypothalamic neuron excitability and the precise action mechanism involved in such an effect have not been fully understood yet. Therefore, Li+ action on hypothalamic neurons was investigated using a whole-cell patch-clamp technique. In hypothalamic neurons, Li+ increased the GABAergic synaptic activities via action potential independent presynaptic mechanisms. Next, concentration-dependent replacement of Na+ by Li+ in artificial cerebrospinal fluid increased frequencies of GABAergic miniature inhibitory postsynaptic currents without altering their amplitudes. Li+ perfusion induced inward currents in the majority of hypothalamic neurons independent of amino-acids receptor activation. These results suggests that Li+ treatment can directly affect the hypothalamic region of the brain and regulate the release of various neurohormones involved in synchronizing the neuroendocrine axis.

Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry.

BACKGROUND: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood. METHODS: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy. RESULTS: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits. CONCLUSIONS: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.

An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization.

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven N-methyl-D-aspartate receptor-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.

Ghrelin treatment leads to dendritic spine remodeling in hippocampal neurons and increases the expression of specific BDNF-mRNA species.

Ghrelin (Gr) is an orexigenic peptide that acts via its specific receptor, GHSR-1a distributed throughout the brain, being mainly enriched in pituitary, cortex and hippocampus (Hp) modulating a variety of brain functions. Behavioral, electrophysiological and biochemical evidence indicated that Gr modulates the excitability and the synaptic plasticity in Hp. The present experiments were designed in order to extend the knowledge about the Gr effect upon structural synaptic plasticity since morphological and quantitative changes in spine density after Gr administration were analyzed "in vitro" and "in vivo". The results show that Gr administered to hippocampal cultures or stereotactically injected in vivo to Thy-1 mice increases the density of dendritic spines (DS) being the mushroom type highly increased in secondary and tertiary extensions. Spines classified as thin type were increased particularly in primary extensions. Furthermore, we show that Gr enhances selectively the expression of BDNF-mRNA species.

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning.

Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABAB receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice.SIGNIFICANCE STATEMENT Prolonged exposure to drugs of abuse triggers neuroadaptations that promote core features of addiction. Understanding these neuroadaptations and their implications may suggest interventions capable of preventing or treating addiction. While previous work showed that repeated cocaine exposure increased the excitability of pyramidal neurons in the prelimbic cortex (PL), the behavioral implications of this neuroadaptation remained unclear. Here, we used neuron-specific manipulations to evaluate the impact of increased PL pyramidal neuron excitability on PL-dependent behaviors. Acute or persistent excitation of PL pyramidal neurons potentiated cocaine-induced motor activity and disrupted trace fear conditioning, effects replicated by selective excitation of the PL projection to the VTA. Our work suggests that hyperexcitability of this projection drives key behavioral hallmarks of addiction.

Neocortical Slow Oscillations Implicated in the Generation of Epileptic Spasms.

OBJECTIVE: Epileptic spasms are a hallmark of severe seizure disorders. The neurophysiological mechanisms and the neuronal circuit(s) that generate these seizures are unresolved and are the focus of studies reported here. METHODS: In the tetrodotoxin model, we used 16-channel microarrays and microwires to record electrophysiological activity in neocortex and thalamus during spasms. Chemogenetic activation was used to examine the role of neocortical pyramidal cells in generating spasms. Comparisons were made to recordings from infantile spasm patients. RESULTS: Current source density and simultaneous multiunit activity analyses indicate that the ictal events of spasms are initiated in infragranular cortical layers. A dramatic pause of neuronal activity was recorded immediately prior to the onset of spasms. This preictal pause is shown to share many features with the down states of slow wave sleep. In addition, the ensuing interictal up states of slow wave rhythms are more intense in epileptic than control animals and occasionally appear sufficient to initiate spasms. Chemogenetic activation of neocortical pyramidal cells supported these observations, as it increased slow oscillations and spasm numbers and clustering. Recordings also revealed a ramp-up in the number of neocortical slow oscillations preceding spasms, which was also observed in infantile spasm patients. INTERPRETATION: Our findings provide evidence that epileptic spasms can arise from the neocortex and reveal a previously unappreciated interplay between brain state physiology and spasm generation. The identification of neocortical up states as a mechanism capable of initiating epileptic spasms will likely provide new targets for interventional therapies. ANN NEUROL 2021;89:226-241.

Crocin attenuates the granular cells damages on the dentate gyrus and pyramidal neurons in the CA3 regions of the hippocampus and frontal cortex in the rat model of Alzheimer's disease.

Amyloid ß-peptides (Aß) are considered as a major hallmark of Alzheimer's disease (AD) that can induce synaptic loss and apoptosis in brain regions, particularly in the cortex and the hippocampus. Evidence suggests that crocin, as the major component of saffron, can exhibit neuromodulatory effects in AD. However, specific data related to their efficacy to attenuate the synaptic loss and neuronal death in animal models of AD are limited. Hence, we investigated the efficacy of crocin in the CA3 and dentate gyrus (DG) regions of the hippocampus and also in frontal cortex neurons employing a rat model of AD. Male Wistar rats were randomly divided into control, sham, AD model, crocin, and AD model + crocin groups, with 8 rats per group. AD model was established by injecting Aß1-42 into the frontal cortex rats, and thereafter the rats were administrated by crocin (30 mg/kg) for a duration of 12-day. The number of live cells, neuronal arborization and apoptosis were measured using a Cresyl violet, Golgi-Cox and TUNEL staining, respectively. Results showed that, the number of live cells in the hippocampus pyramidal neurons in the CA3 and granular cells in the DG regions of the AD rats significantly decreased, which was significantly rescued by crocin. Compared with the control group, the axonal, spine and dendrites arborization in the frontal cortex and CA3 region of the AD model group significantly decreased. The crocin could significantly reverse this arborization loss in the AD rats (P < 0.05). The apoptotic cell number in the CA3 and DG regions in the AD model group was significantly higher than that of the control group (P < 0.05), while crocin significantly decreased the apoptotic cell number in the AD group (P < 0.05). Conclusion. Crocin can improve the synaptic loss and neuronal death of the AD rats possibly by reducing the neuronal apoptosis.

Iron Deficiency and Iron Excess Differently Affect Dendritic Architecture of Pyramidal Neurons in the Hippocampus of Piglets.

BACKGROUND: Both iron deficiency and overload may adversely affect neurodevelopment. OBJECTIVES: The study assessed how changes in early-life iron status affect iron homeostasis and cytoarchitecture of hippocampal neurons in a piglet model. METHODS: On postnatal day (PD) 1, 30 Hampshire × Yorkshire crossbreed piglets (n = 15/sex) were stratified by sex and litter and randomly assigned to experimental groups receiving low (L-Fe), adequate (A-Fe), or high (H-Fe) levels of iron supplement during the pre- (PD1-21) and postweaning periods (PD22-35). Pigs in the L-Fe, A-Fe, and H-Fe groups orally received 0, 1, and 30 mg Fe · kg weight-1 · d-1 preweaning and were fed a diet containing 30, 125, and 1000 mg Fe/kg postweaning, respectively. Heme indexes were analyzed weekly, and gene and protein expressions of iron regulatory proteins in duodenal mucosa, liver, and hippocampus were analyzed through qRT-PCR and western blot, respectively, on PD35. Hippocampal neurons stained using the Golgi-Cox method were traced and their dendritic arbors reconstructed in 3-D using Neurolucida. Dendritic complexity was quantified using Sholl and branch order analyses. RESULTS: Pigs in the L-Fe group developed iron deficiency anemia (hemoglobin = 8.2 g/dL, hematocrit = 20.1%) on PD35 and became stunted during week 5 with lower final body weight than H-Fe group pigs (6.6 compared with 9.6 kg, P < 0.05). In comparison with A-Fe, H-Fe increased hippocampal ferritin expression by 38% and L-Fe decreased its expression by 52% (P < 0.05), suggesting altered hippocampal iron stores. Pigs in the H-Fe group had greater dendritic complexity in CA1/3 pyramidal neurons than L-Fe group pigs as shown by more dendritic intersections with Sholl rings (P ≤ 0.04) and a greater number of dendrites (P ≤ 0.016). CONCLUSIONS: In piglets, the developing hippocampus is susceptible to perturbations by dietary iron, with deficiency and overload differentially affecting dendritic arborization.

Discovery of a Recombinant Human Monoclonal Immunoglobulin G Antibody Against α-Latrotoxin From the Mediterranean Black Widow Spider (Latrodectus tredecimguttatus).

Widow spiders are among the few spider species worldwide that can cause serious envenoming in humans. The clinical syndrome resulting from Latrodectus spp. envenoming is called latrodectism and characterized by pain (local or regional) associated with diaphoresis and nonspecific systemic effects. The syndrome is caused by α-latrotoxin, a ~130 kDa neurotoxin that induces massive neurotransmitter release. Due to this function, α-latrotoxin has played a fundamental role as a tool in the study of neuroexocytosis. Nevertheless, some questions concerning its mode of action remain unresolved today. The diagnosis of latrodectism is purely clinical, combined with the patient's history of spider bite, as no analytical assays exist to detect widow spider venom. By utilizing antibody phage display technology, we here report the discovery of the first recombinant human monoclonal immunoglobulin G antibody (TPL0020_02_G9) that binds α-latrotoxin from the Mediterranean black widow spider (Latrodectus tredecimguttatus) and show neutralization efficacy ex vivo. Such antibody can be used as an affinity reagent for research and diagnostic purposes, providing researchers with a novel tool for more sophisticated experimentation and analysis. Moreover, it may also find therapeutic application in future.

Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel.

CLC-2 is a voltage-gated chloride channel that is widely expressed in mammalian tissues. In the central nervous system, CLC-2 appears in neurons and glia. Studies to define how this channel contributes to normal and pathophysiological function in the central nervous system raise questions that remain unresolved, in part due to the absence of precise pharmacological tools for modulating CLC-2 activity. Herein, we describe the development and optimization of AK-42, a specific small-molecule inhibitor of CLC-2 with nanomolar potency (IC50 = 17 ± 1 nM). AK-42 displays unprecedented selectivity (>1,000-fold) over CLC-1, the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 61 common channels, receptors, and transporters expressed in brain tissue. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. In electrophysiological recordings of mouse CA1 hippocampal pyramidal neurons, AK-42 acutely and reversibly inhibits CLC-2 currents; no effect on current is observed on brain slices taken from CLC-2 knockout mice. These results establish AK-42 as a powerful tool for investigating CLC-2 neurophysiology.

Pycnogenol® Supplementation Attenuates Memory Deficits and Protects Hippocampal CA1 Pyramidal Neurons via Antioxidative Role in a Gerbil Model of Transient Forebrain Ischemia.

Pycnogenol® (an extract of the bark of French maritime pine tree) is used for dietary supplement and known to have excellent antioxidative efficacy. However, there are few reports on neuroprotective effect of Pycnogenol® supplementation and its mechanisms against ischemic injury following transient forebrain ischemia (TFI) in gerbils. Now, we examined neuroprotective effect and its mechanisms of Pycnogenol® in the gerbils with 5-min TFI, which evokes a significant death (loss) of pyramidal cells located in the cornu ammonis (CA1) region of gerbil hippocampus from 4-5 days post-TFI. Gerbils were pretreated with 30, 40, and 50 mg/kg of Pycnogenol® once a day for 7 days before TFI surgery. Treatment with 50 mg/kg, not 30 or 40 mg/kg, of Pycnogenol® potently protected learning and memory, as well as CA1 pyramidal cells, from ischemic injury. Treatment with 50 mg/kg Pycnogenol® significantly enhanced immunoreactivity of antioxidant enzymes (superoxide dismutases and catalase) in the pyramidal cells before and after TFI induction. Furthermore, the treatment significantly reduced the generation of superoxide anion, ribonucleic acid oxidation and lipid peroxidation in the pyramidal cells. Moreover, interestingly, its neuroprotective effect was abolished by administration of sodium azide (a potent inhibitor of SODs and catalase activities). Taken together, current results clearly indicate that Pycnogenol® supplementation can prevent neurons from ischemic stroke through its potent antioxidative role.

Mu-Opioids Suppress GABAergic Synaptic Transmission onto Orbitofrontal Cortex Pyramidal Neurons with Subregional Selectivity.

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion-specific manner. However, it is unknown how mu-opioid signaling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in vitro patch-clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist DAMGO produced a concentration-dependent inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long lasting and not reversed on washout of DAMGO or by application of the mu-opioid receptor antagonist CTAP, suggesting an inhibitory long-term depression (LTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/protein kinase A (PKA) signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.SIGNIFICANCE STATEMENT Considering that both the orbitofrontal cortex (OFC) and the opioid system regulate reward, motivation, and food intake, understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Second, mu-opioids recruit parvalbumin inputs to suppress inhibitory synaptic transmission in the mOFC. Third, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

Schisandra Extract and Ascorbic Acid Synergistically Enhance Cognition in Mice Through Modulation of Mitochondrial Respiration.

Cognitive decline is observed in aging and neurodegenerative diseases, including Alzheimer's disease (AD) and dementia. Intracellular energy produced via mitochondrial respiration is used in the regulation of synaptic plasticity and structure, including dendritic spine length and density, as well as for the release of neurotrophic factors involved in learning and memory. To date, a few synthetic agents for improving mitochondrial function have been developed for overcoming cognitive impairment. However, no natural compounds that modulate synaptic plasticity by directly targeting mitochondria have been developed. Here, we demonstrate that a mixture of Schisandra chinensis extract (SCE) and ascorbic acid (AA) improved cognitive function and induced synaptic plasticity-regulating proteins by enhancing mitochondrial respiration. Treatment of embryonic mouse hippocampal mHippoE-14 cells with a 4:1 mixture of SCE and AA increased basal oxygen consumption rate. We found that mice injected with the SCE-AA mixture showed enhanced learning and memory and recognition ability. We further observed that injection of the SCE-AA mixture in mice significantly increased expression of postsynaptic density protein 95 (PSD95), an increase that was correlated with enhanced brain-derived neurotrophic factor (BDNF) expression. These results demonstrate that a mixture of SCE and AA improves mitochondrial function and memory, suggesting that this natural compound mixture could be used to alleviate AD and aging-associated memory decline.

General Anesthesia Decouples Cortical Pyramidal Neurons.

The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.

Muscarinic and Nicotinic Modulation of Neocortical Layer 6A Synaptic Microcircuits Is Cooperative and Cell-Specific.

Acetylcholine (ACh) is known to regulate cortical activity during different behavioral states, for example, wakefulness and attention. Here we show a differential expression of muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs) in different layer 6A (L6A) pyramidal cell (PC) types of somatosensory cortex. At low concentrations, ACh induced a persistent hyperpolarization in corticocortical (CC) but a depolarization in corticothalamic (CT) L6A PCs via M 4 and M1 mAChRs, respectively. At ~ 1 mM, ACh depolarized exclusively CT PCs via α4ß2 subunit-containing nAChRs without affecting CC PCs. Miniature EPSC frequency in CC PCs was decreased by ACh but increased in CT PCs. In synaptic connections with a presynaptic CC PC, glutamate release was suppressed via M4 mAChR activation but enhanced by nAChRs via α4ß2 nAChRs when the presynaptic neuron was a CT PC. Thus, in L6A, the interaction of mAChRs and nAChRs results in an altered excitability and synaptic release, effectively strengthening CT output while weakening CC synaptic signaling.