Tracking perceived stress, anxiety, and depression in daily life: a double-downward spiral process.

Introduction: Previous studies using retrospective questionnaires have suggested a complex relationship between perceived stress and related negative emotions and emphasized their importance in mental health. However, how daily perceived stress, anxiety, and depression interact dynamically in a natural context remains largely unexplored. Methods: This study conducted a longitudinal survey that applied experience sampling methodology to data from 141 Chinese college students (58% women, mean age = 20.1 ± 1.63 years). Results: The hierarchical linear models confirmed that daily perceived stress and negative emotions (i.e., perceived depression and anxiety) could reciprocally reinforce one another with the characteristic dynamics of a cognitive-emotional downward spiral. Additionally, anxiety and depression could further circularly aggravate each other imminently. These two intertwined downward-spiral processes constitute a double-downward-spiral model. Discussion: The findings contribute to a better understanding of the interactive mechanisms underlying perceived stress and its related negative emotions in everyday life and highlight the significance of early emotion regulation and stress relief in healthy people.

Layer-specific impairment in the developing lateral entorhinal cortex of immune-challenged Disc1+/- mice.

Cognitive deficits in mental disorders result from dysfunctional activity in large-scale brain networks centred around the hippocampus and the prefrontal cortex. Dysfunctional activity emerges early during development and precedes the cognitive disabilities. The prefrontal-hippocampal network is driven by a prominent input from the lateral entorhinal cortex. We have previously shown that during early development, the entorhinal drive of the prefrontal-hippocampal network is impaired in a mouse model of mental disorders, yet the cellular substrate of this impairment is still poorly understood. Here, we address this question by a detailed characterization of projection neurons across the layers of the lateral entorhinal cortex in immune-challenged Disc1+/- mice at the beginning of the second postnatal week. We found that the activity and morphology of neurons in layers 2b and 3, which project to the hippocampus, are impaired. Neurons in layer 2b show increased spike-frequency adaptation, whereas neurons in layer 3 have reduced dendritic complexity but increased spike density. These findings identify the developmental alterations of entorhinal-hippocampal communication that underlie network dysfunction in immune-challenged Disc1+/- mice. KEY POINTS: Neonatal immune-challenged Disc1+/- mice show layer-specific changes in the lateral entorhinal cortex. Entorhinal layer 2b pyramidal neurons have increased spike-frequency adaptation. Reduced dendritic complexity but increased spine density characterize layer 3 pyramidal neurons.

Dynamics and control strategy for a delayed viral infection model.

In this paper, we derive a delayed epidemic model to describe the characterization of cytotoxic T lymphocyte (CTL)-mediated immune response against virus infection. The stability of equilibria and the existence of Hopf bifurcation are analysed. Theoretical results reveal that if the basic reproductive number is greater than 1, the positive equilibrium may lose its stability and the bifurcated periodic solution occurs when time delay is taken as the bifurcation parameter. Furthermore, we investigate an optimal control problem according to the delayed model based on the available therapy for hepatitis B infection. With the aim of minimizing the infected cells and viral load with consideration for the treatment costs, the optimal solution is discussed analytically. For the case when periodic solution occurs, numerical simulations are performed to suggest the optimal therapeutic strategy and compare the model-predicted consequences.

Sparser and Less Efficient Hippocampal-Prefrontal Projections account for Developmental Network Dysfunction in a Model of Psychiatric Risk Mediated by Gene-Environment Interaction.

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.

Developmental decrease of entorhinal-hippocampal communication in immune-challenged DISC1 knockdown mice.

The prefrontal-hippocampal dysfunction that underlies cognitive deficits in mental disorders emerges during early development. The lateral entorhinal cortex (LEC) is tightly interconnected with both prefrontal cortex (PFC) and hippocampus (HP), yet its contribution to the early dysfunction is fully unknown. Here we show that mice that mimic the dual genetic (G) -environmental (E) etiology (GE mice) of psychiatric risk have poor LEC-dependent recognition memory at pre-juvenile age and abnormal communication within LEC-HP-PFC networks throughout development. These functional and behavioral deficits relate to sparser projections from LEC to CA1 and decreased efficiency of axonal terminals to activate the hippocampal circuits in neonatal GE mice. In contrast, the direct entorhinal drive to PFC is not affected, yet the PFC is indirectly compromised, as target of the under-activated HP. Thus, the entorhinal-hippocampal circuit is already impaired from neonatal age on in GE mice.

Angiotensin II induces cognitive decline and anxiety-like behavior via disturbing pattern of theta-gamma oscillations.

Hypertension is the most common chronic disease accompanied by cognitive decline and anxiety-like behavior. Angiotensin II (Ang II) induces hypertension by activating angiotensin II receptor subtype 1 (AT1R). The purpose of the study was to examine the potential underlying mechanism of alterations in cognition and anxiety-like behavior induced by Ang II. Adult C57 mice were intraperitoneal injected with either 1 mg/kg/d Ang II or saline individually for 14 consecutive days. Ang II resulted in cognitive decline and anxious like behavior in C57 mice. Moreover, Ang II disturbed bidirectional synaptic plasticity and neural oscillation coupling between high theta and gamma on PP (perforant pathway)-DG (dentate gyrus) pathway. In addition, Ang II decreased the expression of N-methyl-d-aspartate receptor (NR) 2A and NR 2B and increased the expression of GABAAR α1. The data suggest that Ang II disturb neural oscillations via altering excitatory and inhibitory (E/I) balance and eventually damage cognition and anxiety-like behavior in mice.

Knock-Down of Hippocampal DISC1 in Immune-Challenged Mice Impairs the Prefrontal-Hippocampal Coupling and the Cognitive Performance Throughout Development.

Disrupted-in-schizophrenia 1 (DISC1) gene represents an intracellular hub of developmental processes. When combined with early environmental stressors, such as maternal immune activation, but not in the absence of thereof, whole-brain DISC1 knock-down leads to memory and executive deficits as result of impaired prefrontal-hippocampal communication throughout development. While synaptic dysfunction in neonatal prefrontal cortex (PFC) has been recently identified as one source of abnormal long-range coupling, the contribution of hippocampus (HP) is still unknown. Here, we aim to fill this knowledge gap by combining in vivo electrophysiology and optogenetics with morphological and behavioral assessment of immune-challenged mice with DISC1 knock-down either in the whole brain (GE) or restricted to pyramidal neurons in hippocampal CA1 area (GHPE). We found abnormal network activity, sharp-waves, and neuronal firing in CA1 that complement the deficits in upper layer of PFC. Moreover, optogenetic activating CA1 pyramidal neurons fails to activate the prefrontal local circuits. These deficits that persist till prejuvenile age relate to dendrite sparsification and loss of spines of CA1 pyramidal neurons. As a long-term consequence, DISC1 knock-down in HP leads to poorer recognition memory at prejuvenile age. Thus, DISC1-controlled developmental processes in HP in immune-challenged mice are critical for circuit function and cognitive behavior.

Enriched Environment and Social Isolation Affect Cognition Ability via Altering Excitatory and Inhibitory Synaptic Density in Mice Hippocampus.

The purpose of the study was to examine whether the underlying mechanism of the alteration of cognitive ability and synaptic plasticity induced by the housing environment is associated with the balance of excitatory/inhibitory synaptic density. Enriched environment (EE) and social isolation (SI) are two different housing environment, and one is to give multiple sensory environments, the other is to give monotonous and lonely environment. Male 4-week-old C57 mice were divided into three groups: CON, EE and SI. They were housed in the different cage until 3 months of age. Morris water maze and novel object recognition were performed. Long term potentiation (LTP), depotentiation (DEP) and local field potentials were recorded in the hippocampal perforant pathway and dentate gyrus (DG) region. The data showed that EE enhanced the ability of spatial learning, reversal learning and memory as well as LTP/DEP in the hippocampal DG region. Meanwhile, SI reduced those abilities and the level of LTP/DEP. Moreover, there were higher couplings of both phase-amplitude and phase-phase in the EE group, and lower couplings of them in the SI group compared to that in the CON group. Western blot and immunofluorescence analysis showed that EE significantly enhanced the level of PSD-95, NR2B and DCX; however, SI reduced them but increased GABAARα1 and decreased DCX levels. The data suggests that the cognitive functions, synaptic plasticity, neurogenesis and neuronal oscillatory patterns were significantly impacted by housing environment via possibly changing the balance of excitatory and inhibitory synaptic density.

Cross-Talk of Low-Level Sensory and High-Level Cognitive Processing: Development, Mechanisms, and Relevance for Cross-Modal Abilities of the Brain.

The emergence of cross-modal learning capabilities requires the interaction of neural areas accounting for sensory and cognitive processing. Convergence of multiple sensory inputs is observed in low-level sensory cortices including primary somatosensory (S1), visual (V1), and auditory cortex (A1), as well as in high-level areas such as prefrontal cortex (PFC). Evidence shows that local neural activity and functional connectivity between sensory cortices participate in cross-modal processing. However, little is known about the functional interplay between neural areas underlying sensory and cognitive processing required for cross-modal learning capabilities across life. Here we review our current knowledge on the interdependence of low- and high-level cortices for the emergence of cross-modal processing in rodents. First, we summarize the mechanisms underlying the integration of multiple senses and how cross-modal processing in primary sensory cortices might be modified by top-down modulation of the PFC. Second, we examine the critical factors and developmental mechanisms that account for the interaction between neuronal networks involved in sensory and cognitive processing. Finally, we discuss the applicability and relevance of cross-modal processing for brain-inspired intelligent robotics. An in-depth understanding of the factors and mechanisms controlling cross-modal processing might inspire the refinement of robotic systems by better mimicking neural computations.

Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment.

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.

Developmental dysfunction of prefrontal-hippocampal networks in mouse models of mental illness.

Despite inherent difficulties to translate human cognitive phenotype into animals, a large number of animal models for psychiatric disorders, such as schizophrenia, have been developed over the last decades. To which extent they reproduce common patterns of dysfunction related to mental illness and abnormal processes of maturation is still largely unknown. While the devastating symptoms of disease are firstly detectable in adulthood, they are considered to reflect profound miswiring of brain circuitry as result of abnormal development. To reveal whether different disease models share common dysfunction early in life, we investigate the prefrontal-hippocampal communication at neonatal age in (a) mice mimicking the abnormal genetic background (22q11.2 microdeletion, DISC1 knockdown), (b) mice mimicking the challenge by environmental stressors (maternal immune activation during pregnancy), (c) mice mimicking the combination of both aetiologies (dual-hit models) and pharmacological mouse models. Simultaneous extracellular recordings in vivo from all layers of prelimbic subdivision (PL) of prefrontal cortex (PFC) and CA1 area of intermediate/ventral hippocampus (i/vHP) show that network oscillations have a more fragmented structure and decreased power mainly in neonatal mice that mimic both genetic and environmental aetiology of disease. These mice also show layer-specific firing deficits in PL. Similar early network dysfunction was present in mice with 22q11.2 microdeletion. The abnormal activity patterns are accompanied by weaker synchrony and directed interactions within prefrontal-hippocampal networks. Thus, only severe genetic defects or combined genetic environmental stressors are disruptive enough for reproducing the early network miswiring in mental disorders.

Transient Knock-Down of Prefrontal DISC1 in Immune-Challenged Mice Causes Abnormal Long-Range Coupling and Cognitive Dysfunction throughout Development.

Compromised brain development has been hypothesized to account for mental illness. This concept was underpinned by the function of the molecule disrupted-in-schizophrenia 1 (DISC1), which represents an intracellular hub of developmental processes and has been related to cognitive dysfunction in psychiatric disorders. Mice with whole-brain DISC1 knock-down show impaired prefrontal-hippocampal function and cognitive abilities throughout development and at adulthood, especially when combined with early environmental stressors, such as maternal immune activation (MIA). However, the contribution of abnormal DISC1-driven maturation of either prefrontal cortex (PFC) or hippocampus (HP) to these deficits is still unknown. Here, we use in utero electroporation to restrict the DISC1 knock-down to prefrontal layer II/III pyramidal neurons during perinatal development and expose these mice to MIA as an environmental stressor (dual-hit GPFCE mice, both sexes). Combining in vivo electrophysiology and neuroanatomy with behavioral testing, we show that GPFCE mice at neonatal age have abnormal patterns of oscillatory activity and firing in PFC, but not HP. Abnormal firing rates in PFC of GPFCE mice relate to sparser dendritic arborization and lower spine density. Moreover, the long-range coupling within prefrontal-hippocampal networks is decreased at this age. The transient prefrontal DISC1 knock-down was sufficient to permanently perturb the prefrontal-hippocampal communication and caused poorer recognition memory performance at pre-juvenile age. Thus, developmental dysfunction of prefrontal circuitry causes long-lasting disturbances related to mental illness.SIGNIFICANCE STATEMENT Hypofrontality is considered a main cause of cognitive deficits in mental disorders, yet the underlying mechanisms are still largely unknown. During development, long before the emergence of disease symptoms, the functional coupling within the prefrontal-hippocampal network, which is the core brain circuit involved in cognitive processing, is reduced. To assess to which extent impaired prefrontal development contributes to the early dysfunction, immune-challenged mice with transient DISC1 knock-down confined to PFC were investigated in their prefrontal-hippocampal communication throughout development by in vivo electrophysiology and behavioral testing. We show that perturbing developmental processes of prefrontal layer II/III pyramidal neurons is sufficient to diminish prefrontal-hippocampal coupling and decrease the cognitive performance throughout development.

Multisensory integration in rodent tactile but not visual thalamus.

Behavioural performance requires a coherent perception of environmental features that address multiple senses. These diverse sensory inputs are integrated in primary sensory cortices, yet it is still largely unknown whether their convergence occurs even earlier along the sensory tract. Here we investigate the role of putatively modality-specific first-order (FO) thalamic nuclei (ventral posteromedial nucleus (VPM), dorsal lateral geniculate nucleus (dLGN)) and their interactions with primary sensory cortices (S1, V1) for multisensory integration in pigmented rats in vivo. We show that bimodal stimulation (i.e. simultaneous light flash and whisker deflection) enhances sensory evoked activity in VPM, but not dLGN. Moreover, cross-modal stimuli reset the phase of thalamic network oscillations and strengthen the coupling efficiency between VPM and S1, but not between dLGN and V1. Finally, the information flow from VPM to S1 is enhanced. Thus, FO tactile, but not visual, thalamus processes and relays sensory inputs from multiple senses, revealing a functional difference between sensory thalamic nuclei during multisensory integration.

Neural oscillations as a bridge between glutamatergic system and emotional behaviors in simulated microgravity-induced mice.

This study aims to investigate if neural oscillations can play a role as a bridge between the alteration of glutamatergic system and emotional behaviors in simulated microgravity (SM) mice. Adult male C57BL/6J mice were randomly divided into two groups: SM and control groups. The animal model was established by hindlimb unloading (HU). The mice were exposed to HU continued for 14days. Weight and sucrose consumption were measured. The degree of anxious and depressive was evaluated by Open field test and Elevated plus maze test. Local field potentials were recorded in the hippocampal perforant path (PP) and dentate gyrus (DG) regions. The NMDAR2A/2B (NR2A/2B) subunits expression and glutamate level were measured by Western and high performance liquid chromatography (HPLC), respectively. After 14days, SM mice exhibited depressive-like and anxiety-like behaviors, while the expression of NR2A/2B subunits and the glutamate level were significantly decreased in the SM group. Moreover, the power distribution of theta (3-8Hz) was decreased by HU, which further significantly attenuated the identical-frequency strength of phase synchronization and the neural information flow at theta rhythm on the PP-DG pathway. The theta-gamma phase synchronization strength was also significantly reduced by HU. The data imply that the neural oscillations measurements is a sign of the emotional behaviors impairment and the glutamatergic system change induced by HU.

Leonurine ameliorates cognitive dysfunction via antagonizing excitotoxic glutamate insults and inhibiting autophagy.

BACKGROUND: Chronic cerebral hypoperfusion is related with cognitive deficits in different types of dementia. PURPOSE: In this study, we aimed to investigate the effect and potential mechanisms of leonurine on chronic cerebral hypoperfusion both in vitro and in vivo. STUDY DESIGN: Chronic cerebral hypoperfusion was duplicated by oxygen-glucose deprivation (OGD) in vitro and by ligation of bilateral common carotid arteries (2-VO) in vivo. METHODS: In in vitro study, there were control group, OGD group, OGD+ 100µM leonurin group, and OGD+ 10µM donepezil group. The spontaneous excitatory postsynaptic current amplitude and frequency were recorded. In in vivo study, the chronic cerebral hypoperfusion model was induced by ligated bilateral common carotid arteries. Rats were randomly divided into Sham group, 2-VO group, 2-VO+ 60mg/kg/day leonurine group, and 2-VO+ 4mg/kg/day donepezil group. After three weeks, the Morris water maze and Long-term depression recording were observed. Then N-methyl-D-aspartate receptor-associated proteins and autophagy-associated proteins were detected by Western blot assay. RESULTS: In in vitro experiment, results showed that leonurine could obviously attenuate the spontaneous excitatory postsynaptic current amplitude and frequency on pyramidal neurons. In in vivo experiment, leonurine significantly decreased levels of glutamate and hydrogen peroxide, improved both the cognitive flexibility and the spatial learning and memory abilities. Moreover, leonurine obviously enhanced long-term depression, elevated the ratio of N-methyl-D-aspartate receptor 2A/2B, and decreased the expression of postsynaptic density protein-95. Interestingly, the ratio of LC3II/LC3I and beclin-1 expression were markedly down-regulated by leonurine. CONCLUSION: These findings suggest that leonurine ameliorates cognitive dysfunction at least partly via antagonizing excitotoxic glutamate insults and inhibiting autophagy. Furthermore, it might become a potential drug candidate of chronic cerebral hyperfusion in future.

A Precise Annotation of Phase-Amplitude Coupling Intensity.

Neuronal information can be coded in different temporal and spatial scales. Cross-frequency coupling of neuronal oscillations, especially phase-amplitude coupling (PAC), plays a critical functional role in neuronal communication and large scale neuronal encoding. Several approaches have been developed to assess PAC intensity. It is generally agreed that the PAC intensity relates to the uneven distribution of the fast oscillation amplitude conditioned on the slow oscillation phase. However, it is still not clear what the PAC intensity exactly means. In the present study, it was found that there were three types of interferential signals taking part in PAC phenomenon. Based on the classification of interferential signals, the conception of PAC intensity is theoretically annotated as the proportion of slow or fast oscillation that is involved in a related PAC phenomenon. In order to make sure that the annotation is proper to some content, simulation data are constructed and then analyzed by three PAC approaches. These approaches are the mean vector length (MVL), the modulation index (MI), and a new permutation mutual information (PMI) method in which the permutation entropy and the information theory are applied. Results show positive correlations between PAC values derived from all three methods and the suggested intensity. Finally, the amplitude distributions, i.e. the phase-amplitude plots, obtained from different PAC intensities show that the annotation proposed in the study is in line with the previous understandings.

Effects of Dopamine and Serotonin Systems on Modulating Neural Oscillations in Hippocampus-Prefrontal Cortex Pathway in Rats.

Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1-mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1-mPFC network.

Hydrogen Sulfide Prevents Synaptic Plasticity from VD-Induced Damage via Akt/GSK-3ß Pathway and Notch Signaling Pathway in Rats.

Our previous study has demonstrated that hydrogen sulfide (H2S) attenuates neuronal injury induced by vascular dementia (VD) in rats, but the mechanism is still poorly understood. In this study, we aimed to investigate whether the neuroprotection of H2S was associated with synaptic plasticity and try to interpret the potential underlying mechanisms. Adult male Wistar rats were suffered the ligation of bilateral common carotid arteries. At 24 h after surgery, rats were administered intraperitoneally with sodium hydrosulfide (NaHS, 5.6 mg·kg(-1)·day(-1)), a H2S donor, for 3 weeks in the VD+NaHS group and treated intraperitoneally with saline in the VD group respectively. Our results demonstrated that NaHS significantly decreased the level of glutamate. It obviously ameliorated cognitive flexibility as well as the spatial learning and memory abilities by Morris water maze. Moreover, NaHS significantly improved the long-term depression (LTD), and was able to elevate the expression of N-methyl-D-aspartate receptor subunit 2A, which plays a pivotal role in synaptic plasticity. Interestingly, NaHS decreased the phosphorylation of Akt, and it could maintain the activity of glycogen synthase kinase-3ß (GSK-3ß). Surprisingly, NaHS triggered the canonical Notch pathway by increasing expressions of Jagged-1 and Hes-1. These findings suggest that NaHS prevents synaptic plasticity from VD-induced damage partly via Akt/GSK-3ß pathway and Notch signaling pathway.Hydrogen sulfide modulated the ratio of NMDAR 2A/2B and improved the synaptic plasticity via Akt/GSK-3ß pathway and Notch signaling pathway in VD rats.

Effects of Hydrogen Sulfide on Modulation of Theta-Gamma Coupling in Hippocampus in Vascular Dementia Rats.

Our previous study showed that hydrogen sulfide (H2S) could alleviate the cognitive deficits in vascular dementia (VD) rats associated with the improvement of synaptic plasticity. Neural oscillations are reported to interact with each other through either identical-frequency or cross-frequency coupling. This study examined whether impaired neural couplings could be alleviated by H2S in the hippocampal CA3-CA1 of VD rats and explored its possible mechanism. A VD rat model was established by two-vessel occlusion. Sodium hydrosulfide (NaHS), a kind of H2S donor, was administered intraperitoneally (5.6 mg/kg/day) for 3 weeks. Local field potentials were simultaneously collected in the hippocampal CA3 and CA1. The effects of NaHS on the modulation of theta-gamma coupling were evaluated by using the measurements of both phase-phase coupling and phase-amplitude coupling, while several other approaches including behavior, electrophysiology, western blot, immunofluorescence staining were also employed. The results showed that NaHS significantly prevented spatial learning and memory impairments (p < 0.01). NaHS considerably alleviated the impairment of neural coupling in VD rats in an identical-frequency rhythm and between cross-frequency bands. Moreover, the expression of cystathionine-ß-synthase (CBS) was markedly attenuated in VD rats. NaHS elevated the expression of CBS to maintain the intrinsic balance of H2S. Interestingly, it was observed that NaHS increased the protein expression of N-methyl-D-aspartic acid receptor 2A (NMDAR2A) in VD rats. In conclusion, the data suggest that NaHS played the neuroprotective role partly via modulating the expression of NMDAR2A in order to alleviate the impairments of neural couplings in VD rats.

Impairment of cognitive function and synaptic plasticity associated with alteration of information flow in theta and gamma oscillations in melamine-treated rats.

Changes of neural oscillations at a variety of physiological rhythms are effectively associated with cognitive performance. The present study investigated whether the directional indices of neural information flow (NIF) could be used to symbolize the synaptic plasticity impairment in hippocampal CA3-CA1 network in a rat model of melamine. Male Wistar rats were employed while melamine was administered at a dose of 300 mg/kg/day for 4 weeks. Behavior was measured by the Morris water maze(MWM)test. Local field potentials (LFPs) were recorded before long-term potentiation (LTP) induction. Generalized partial directed coherence (gPDC) and phase-amplitude coupling conditional mutual information (PAC_CMI) were used to measure the unidirectional indices in both theta and low gamma oscillations (LG, ~ 30-50 Hz). Our results showed that melamine induced the cognition deficits consistent with the reduced LTP in CA1 area. Phase locking values (PLVs) showed that the synchronization between CA3 and CA1 in both theta and LG rhythms was reduced by melamine. In both theta and LG rhythms, unidirectional indices were significantly decreased in melamine treated rats while a similar variation trend was observed in LTP reduction, implying that the effects of melamine on cognitive impairment were possibly mediated via profound alterations of NIF on CA3-CA1 pathway in hippocampus. The results suggested that LFPs activities at these rhythms were most likely involved in determining the alterations of information flow in the hippocampal CA3-CA1 network, which might be associated with the alteration of synaptic transmission to some extent.