Local Network Activity Research Articles

Congenital deafness reduces alpha-gamma cross-frequency coupling in the auditory cortex

Neurons within a neuronal network can be grouped by bottom-up and top-down influences using synchrony in neuronal oscillations. This creates the representation of perceptual objects from sensory features. Oscillatory activity can be differentiated into stimulus-phase-locked (evoked) and non-phase-locked (induced). The former is mainly determined by sensory input, the latter by higher-level (cortical) processing. Effects of auditory deprivation on cortical oscillations have been studied in congenitally deaf cats (CDCs) using cochlear implant (CI) stimulation. CI-induced alpha, beta, and gamma activity were compromised in the auditory cortex of CDCs. Furthermore, top-down information flow between secondary and primary auditory areas in hearing cats, conveyed by induced alpha oscillations, was lost in CDCs. Here we used the matching pursuit algorithm to assess components of such oscillatory activity in local field potentials recorded in primary field A1. Additionally to the loss of induced alpha oscillations, we also found a loss of evoked theta activity in CDCs. The loss of theta and alpha activity in CDCs can be directly related to reduced high-frequency (gamma-band) activity due to cross-frequency coupling. Here we quantified such cross-frequency coupling in adult 1) hearing-experienced, acoustically stimulated cats (aHCs), 2) hearing-experienced cats following acute pharmacological deafening and subsequent CIs, thus in electrically stimulated cats (eHCs), and 3) electrically stimulated CDCs. We found significant cross-frequency coupling in all animal groups in > 70% of auditory-responsive sites. The predominant coupling in aHCs and eHCs was between theta/alpha phase and gamma power. In CDCs such coupling was lost and replaced by alpha oscillations coupling to delta/theta phase. Thus, alpha/theta oscillations synchronize high-frequency gamma activity only in hearing-experienced cats. The absence of induced alpha and theta oscillations contributes to the loss of induced gamma power in CDCs, thereby signifying impaired local network activity.

Inflammatory processes in the prefrontal cortex induced by systemic immune challenge: Focusing on neurons

Peripheral immune challenge induces neurobiological alterations in the brain and related neuropsychiatric symptoms both in humans and other mammals. One of the best known physiological effects of systemic inflammation is sickness behavior. However, in addition to this depression-like state, there are other cognitive outcomes of peripherally induced neuroinflammation that can be linked to the dysfunction of higher-order cortical areas, such as the prefrontal cortex (PFC). As the physiological activity of the PFC is largely based on the balanced interplay of excitatory pyramidal cells and inhibitory interneurons, it may be hypothesized that neuroinflammatory processes result in a shift of excitatory/inhibitory balance, which is a common hallmark of several neuropsychiatric conditions. Indeed, many data suggest that peripherally induced neuroinflammation is strongly associated with molecular and functional changes in PFC neurons leading to disturbances in their synaptic networks. Different experimental approaches may cause some incongruence in the reviewed data. However, it is commonly agreed that acute systemic inflammation leads to changes in the excitatory/inhibitory balance in the PFC by proinflammatory signaling at the brain borders and in the brain parenchyma. These cellular changes result in altered local and brain-wide network activity inducing disturbances in the top-down control of goal-directed behavior and cognition regulated by the PFC. Lipopolysaccharide (LPS)-treated rodents are the most widely used experimental models of peripherally induced neuroinflammation, so the majority of the reviewed data come from studies utilizing the LPS model. This may limit their general interpretation regarding the neuronal effects of peripheral immune activation. In addition, several biological variables (e.g., sex, age) can influence the PFC effects of systemic immune challenge, not only the nature and severity of immune activation. Therefore, it would be desirable to investigate inflammation-related neuronal changes in the PFC using other models of systemic inflammation as well, and to focus on the targeted fine-tuning of the affected cell types via common molecular mechanisms of the immune and nervous systems.

Structural Organization of Perisomatic Inhibition in the Mouse Medial Prefrontal Cortex.

Perisomatic inhibition profoundly controls neural function. However, the structural organization of inhibitory circuits giving rise to the perisomatic inhibition in the higher-order cortices is not completely known. Here, we performed a comprehensive analysis of those GABAergic cells in the medial prefrontal cortex (mPFC) that provide inputs onto the somata and proximal dendrites of pyramidal neurons. Our results show that most GABAergic axonal varicosities contacting the perisomatic region of superficial (layer 2/3) and deep (layer 5) pyramidal cells express parvalbumin (PV) or cannabinoid receptor type 1 (CB1). Further, we found that the ratio of PV/CB1 GABAergic inputs is larger on the somatic membrane surface of pyramidal tract neurons in comparison with those projecting to the contralateral hemisphere. Our morphologic analysis of in vitro labeled PV+ basket cells (PVBC) and CCK/CB1+ basket cells (CCKBC) revealed differences in many features. PVBC dendrites and axons arborized preferentially within the layer where their soma was located. In contrast, the axons of CCKBCs expanded throughout layers, although their dendrites were found preferentially either in superficial or deep layers. Finally, using anterograde trans-synaptic tracing we observed that PVBCs are preferentially innervated by thalamic and basal amygdala afferents in layers 5a and 5b, respectively. Thus, our results suggest that PVBCs can control the local circuit operation in a layer-specific manner via their characteristic arborization, whereas CCKBCs rather provide cross-layer inhibition in the mPFC.SIGNIFICANCE STATEMENT Inhibitory cells in cortical circuits are crucial for the precise control of local network activity. Nevertheless, in higher-order cortical areas that are involved in cognitive functions like decision-making, working memory, and cognitive flexibility, the structural organization of inhibitory cell circuits is not completely understood. In this study we show that perisomatic inhibitory control of excitatory cells in the medial prefrontal cortex is performed by two types of basket cells endowed with different morphologic properties that provide inhibitory inputs with distinct layer specificity on cells projecting to disparate areas. Revealing this difference in innervation strategy of the two basket cell types is a key step toward understanding how they fulfill their distinct roles in cortical network operations.

Rhythmic calcium ion activity related to glioma growth reveals the mechanism of ion transmission

Rhythmic calcium ion activity related to glioma growth reveals the mechanism of ion transmission

Neuroanatomical predictors of real-time fMRI-based anterior insula regulation. A supervised machine learning study.

Increasing evidence showed that learned control of metabolic activity in selected brain regions can support emotion regulation. Notably, a number of studies demonstrated that neurofeedback-based regulation of fMRI activity in several emotion-related areas leads to modifications of emotional behavior along with changes of neural activity in local and distributed networks, in both healthy individuals and individuals with emotional disorders. However, the current understanding of the neural mechanisms underlying self-regulation of the emotional brain, as well as their relationship with other emotion regulation strategies, is still limited. In this study, we attempted to delineate neuroanatomical regions mediating real-time fMRI-based emotion regulation by exploring whole brain GM and WM features predictive of self-regulation of anterior insula (AI) activity, a neuromodulation procedure that can successfully support emotional brain regulation in healthy individuals and patients. To this aim, we employed a multivariate kernel ridge regression model to assess brain volumetric features, at regional and network level, predictive of real-time fMRI-based AI regulation. Our results showed that several GM regions including fronto-occipital and medial temporal areas and the basal ganglia as well as WM regions including the fronto-occipital fasciculus, tapetum and fornix significantly predicted learned AI regulation. Remarkably, we observed a substantial contribution of the cerebellum in relation to both the most effective regulation run and average neurofeedback performance. Overall, our findings highlighted specific neurostructural features contributing to individual differences of AI-guided emotion regulation. Notably, such neuroanatomical topography partially overlaps with the neurofunctional network associated with cognitive emotion regulation strategies, suggesting common neural mechanisms.

Distinct Dynamics of Theta and Gamma Rhythmicity during Social Interaction Suggest Differential Mode of Action in the Medial Amygdala of Sprague Dawley Rats and C57BL/6J Mice

The medial nucleus of the amygdala (MeA) is known to regulate social behavior. This brain area is functionally positioned in a crossroads between sensory information processing and behavioral modulation. On the one hand, it receives direct chemosensory input from the accessory olfactory bulb. On the other hand, it orchestrates various behavioral outputs via brain-wide projections under the regulation of multiple neuromodulatory systems. Previously, we showed that adult male Sprague Dawley (SD) rats and C57BL/6J mice, the most widely used rodent models in neuroscience research, differ in their dynamics of motivation to interact with a novel same-sex conspecific and that this difference correlates with the level of c-Fos expression in the MeA. Here we used chronically implanted electrodes to compare rhythmic local field potential signals recorded from these animals during free and restricted social interactions. We found a significant induction of rhythmicity in the theta (4–12 Hz) and gamma (30–80 Hz) bands during both free and restricted social interaction in both rats and mice. However, the induction of gamma rhythmicity, thought to reflect activity of local neuronal networks, was significantly higher in rats than mice. Nevertheless, in contrast to rats, mice exhibited induction of rhythmicity, in both the theta and gamma bands, in synchrony with investigation of social, but not object stimuli. These results suggest that during interaction with a novel same-sex conspecific, the MeA of C57BL/6J mice is mostly involved in sensory information processing while in SD rats it is mainly active in modulating the social motivation state of the animal.

Alzheimer-like tau accumulation in dentate gyrus mossy cells induces spatial cognitive deficits by disrupting multiple memory-related signaling and inhibiting local neural circuit.

Abnormal tau accumulation and spatial memory loss constitute characteristic pathology and symptoms of Alzheimer disease (AD). Yet, the intrinsic connections and the mechanism between them are not fully understood. In the current study, we observed a prominent accumulation of the AD‐like hyperphosphorylated and truncated tau (hTau N368) proteins in hippocampal dentate gyrus (DG) mossy cells of 3xTg‐AD mice. Further investigation demonstrated that the ventral DG (vDG) mossy cell‐specific overexpressing hTau for 3 months induced spatial cognitive deficits, while expressing hTau N368 for only 1 month caused remarkable spatial cognitive impairment with more prominent tau pathologies. By in vivo electrophysiological and optic fiber recording, we observed that the vDG mossy cell‐specific overexpression of hTau N368 disrupted theta oscillations with local neural network inactivation in the dorsal DG subset, suggesting impairment of the ventral to dorsal neural circuit. The mossy cell‐specific transcriptomic data revealed that multiple AD‐associated signaling pathways were disrupted by hTau N368, including reduction of synapse‐associated proteins, inhibition of AKT and activation of glycogen synthase kinase‐3β. Importantly, chemogenetic activating mossy cells efficiently attenuated the hTau N368‐induced spatial cognitive deficits. Together, our findings indicate that the mossy cell pathological tau accumulation could induce the AD‐like spatial memory deficit by inhibiting the local neural network activity, which not only reveals new pathogenesis underlying the mossy cell‐related spatial memory loss but also provides a mouse model of Mossy cell‐specific hTau accumulation for drug development in AD and the related tauopathies.

Passive localization of the central sulcus during sleep based on intracranial EEG.

We test the performance of a novel operator-independent EEG-based method for passive identification of the central sulcus (CS) and sensorimotor (SM) cortex. We studied seven patients with intractable epilepsy undergoing intracranial EEG (icEEG) monitoring, in whom CS localization was accomplished by standard methods. Our innovative approach takes advantage of intrinsic properties of the primary motor cortex (MC), which exhibits enhanced icEEG band-power and coherence across the CS. For each contact, we computed a composite power, coherence, and entropy values for activity in the high gamma band (80-115) Hz of 6-10 min of NREM sleep. Statistically transformed EEG data values that did not reach a threshold (th) were set to 0. We computed a metric M based on the transformed values and the mean Euclidian distance of each contact from contacts with Z-scores higher than 0. The last step was implemented to accentuate local network activity. The SM cortex exhibited higher EEG-band-power than non-SM cortex (P < 0.0002). There was no significant difference between the motor/premotor and sensory cortices (P < 0.47). CS was localized in all patients with 0.4 < th < 0.6. The primary hand and leg motor areas showed the highest metric values followed by the tongue motor area. Higher threshold values were specific (94%) for the anterior bank of the CS but not sensitive (42%). Intermediate threshold values achieved an acceptable trade-off (0.4: 89% specific and 70% sensitive).

The developmental changes in intrinsic and synaptic properties of prefrontal neurons enhance local network activity from the second to the third postnatal weeks in mice

The prefrontal cortex (PFC) is characterized by protracted maturation. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unknown. Our study delineates the developmental cellular processes in the mouse medial PFC (mPFC) during the second and the third postnatal weeks and characterizes their contribution to the changes in network activity. We show that spontaneous inhibitory postsynaptic currents (sIPSC) are increased, whereas spontaneous excitatory postsynaptic currents (sEPSC) are reduced from the second to the third postnatal week. Drug application suggested that the increased sEPSC frequency in mPFC at postnatal day 10 (P10) is due to depolarizing γ-aminobutyric acid (GABA) type A receptor function. To further validate this, perforated patch-clamp recordings were obtained and the expression levels of K-Cl cotransporter 2 (KCC2) protein were examined. The reversal potential of IPSCs in response to current stimulation was significantly more depolarized at P10 than P20 while KCC2 expression is decreased. Moreover, the number of parvalbumin-expressing GABAergic interneurons increases and their intrinsic electrophysiological properties significantly mature in the mPFC from P10 to P20. Using computational modeling, we show that the developmental changes in synaptic and intrinsic properties of mPFC neurons contribute to the enhanced network activity in the juvenile compared with neonatal mPFC.

Lateral entorhinal cortex supports the development of prefrontal network activity that bridges temporally discontiguous stimuli

The lateral entorhinal cortex (LEC) is an essential component of the brain circuitry supporting long-term memory by serving as an interface between the hippocampus and neocortex. Dysfunction of the LEC affects sensory coding in the hippocampus, leading to a view that the LEC provides the hippocampus with highly processed sensory information. It remains unclear, however, how the LEC modulates neural processing in the neocortical regions. To address this point, we pharmacologically inactivated the LEC of male rats during a temporal associative learning task and examined its impact on local network activity in one of the LEC's efferent targets, the prelimbic region of the medial prefrontal cortex (mPFC). Rats were exposed to two neutral stimuli, one of which was paired with an aversive eyelid shock over a short temporal delay. The LEC inhibition reduced the expression of anticipatory blinking responses to the reinforced stimuli without increasing responses to nonreinforced stimuli. In control rats, both the reinforced and nonreinforced stimuli evoked a short-lived, wide-band increase in the prelimbic network activity. With learning, the initial increase of gamma-band activity started to extend into the interval between the reinforced neutral stimulus and the eyelid shock. LEC inhibition attenuated the learning-induced sustained activity, without affecting the initial transient activity. These results suggest that the integrity of LEC is necessary for the formation of temporal stimulus associations and its neural correlates in the mPFC. Given the minimal effects on the innate network responses to sensory stimuli, the LEC appears not to be the main source of sensory inputs to the mPFC; rather it may provide a framework that shapes the mPFC network response to behaviorally relevant cues.

Distinct patterns of activity in individual cortical neurons and local networks in primary somatosensory cortex of mice evoked by square-wave mechanical limb stimulation.

Artificial forms of mechanical limb stimulation are used within multiple fields of study to determine the level of cortical excitability and to map the trajectory of neuronal recovery from cortical damage or disease. Square-wave mechanical or electrical stimuli are often used in these studies, but a characterization of sensory-evoked response properties to square-waves with distinct fundamental frequencies but overlapping harmonics has not been performed. To distinguish between somatic stimuli, the primary somatosensory cortex must be able to represent distinct stimuli with unique patterns of activity, even if they have overlapping features. Thus, mechanical square-wave stimulation was used in conjunction with regional and cellular imaging to examine regional and cellular response properties evoked by different frequencies of stimulation. Flavoprotein autofluorescence imaging was used to map the somatosensory cortex of anaesthetized C57BL/6 mice, and in vivo two-photon Ca2+ imaging was used to define patterns of neuronal activation during mechanical square-wave stimulation of the contralateral forelimb or hindlimb at various frequencies (3, 10, 100, 200, and 300 Hz). The data revealed that neurons within the limb associated somatosensory cortex responding to various frequencies of square-wave stimuli exhibit stimulus-specific patterns of activity. Subsets of neurons were found to have sensory-evoked activity that is either primarily responsive to single stimulus frequencies or broadly responsive to multiple frequencies of limb stimulation. High frequency stimuli were shown to elicit more population activity, with a greater percentage of the population responding and greater percentage of cells with high amplitude responses. Stimulus-evoked cell-cell correlations within these neuronal networks varied as a function of frequency of stimulation, such that each stimulus elicited a distinct pattern that was more consistent across multiple trials of the same stimulus compared to trials at different frequencies of stimulation. The variation in cortical response to different square-wave stimuli can thus be represented by the population pattern of supra-threshold Ca2+ transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between neurons.

Reciprocal Lateral Hypothalamic and Raphe GABAergic Projections Promote Wakefulness.

The lateral hypothalamus (LH), together with multiple neuromodulatory systems of the brain, such as the dorsal raphe nucleus (DR), is implicated in arousal, yet interactions between these systems are just beginning to be explored. Using a combination of viral tracing, circuit mapping, electrophysiological recordings from identified neurons, and combinatorial optogenetics in mice, we show that GABAergic neurons in the LH selectively inhibit GABAergic neurons in the DR, resulting in increased firing of a substantial fraction of its neurons that ultimately promotes arousal. These DRGABA neurons are wake active and project to multiple brain areas involved in the control of arousal, including the LH, where their specific activation potently influences local network activity leading to arousal from sleep. Our results show how mutual inhibitory projections between the LH and the DR promote wakefulness and suggest a complex arousal control by intimate interactions between long-range connections and local circuit dynamics.SIGNIFICANCE STATEMENT: Multiple brain systems including the lateral hypothalamus and raphe serotonergic system are involved in the regulation of the sleep/wake cycle, yet the interaction between these systems have remained elusive. Here we show that mutual disinhibition mediated by long range inhibitory projections between these brain areas can promote wakefulness. The main importance of this work relies in revealing the interaction between a brain area involved in autonomic regulation and another in controlling higher brain functions including reward, patience, mood and sensory coding.

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer\u2019s disease

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

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

BackgroundBoth 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. MethodsNeonatal 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. ResultsRepeated, 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. ConclusionsRepeated 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.

A network model of the barrel cortex combined with a differentiator detector reproduces features of the behavioral response to single-neuron stimulation.

The stimulation of a single neuron in the rat somatosensory cortex can elicit a behavioral response. The probability of a behavioral response does not depend appreciably on the duration or intensity of a constant stimulation, whereas the response probability increases significantly upon injection of an irregular current. Biological mechanisms that can potentially suppress a constant input signal are present in the dynamics of both neurons and synapses and seem ideal candidates to explain these experimental findings. Here, we study a large network of integrate-and-fire neurons with several salient features of neuronal populations in the rat barrel cortex. The model includes cellular spike-frequency adaptation, experimentally constrained numbers and types of chemical synapses endowed with short-term plasticity, and gap junctions. Numerical simulations of this model indicate that cellular and synaptic adaptation mechanisms alone may not suffice to account for the experimental results if the local network activity is read out by an integrator. However, a circuit that approximates a differentiator can detect the single-cell stimulation with a reliability that barely depends on the length or intensity of the stimulus, but that increases when an irregular signal is used. This finding is in accordance with the experimental results obtained for the stimulation of a regularly-spiking excitatory cell.

Setting the agenda for food waste prevention – A perspective on local government policymaking

Food waste prevention has gained greater relevance on the political agenda over the last decade. However, the involvement of municipal actors in pushing the issue forward has been comparatively limited. Based on the cases of the German cities of Munich and Cologne, this paper examines the possible approaches to prevent food waste at the municipal level and their relevance on the local agenda. It first proposes a definition of local food waste prevention policies and presents an overview of options for municipal actors. Based on the analysis of own interview data and secondary sources, it then applies Kingdon’s Multiple Streams Framework to gain insights on the agenda-setting processes in the two cities concerning the issue. The results suggest that policy entrepreneurs, a strategic framing, and networking with other political levels favour the rise of food waste prevention on the local agenda. The main hindering factors identified are problem load and budgetary constraints, as well as the lack of strong political interest groups and a perceived spatial mismatch between problem and solutions. The findings provide starting points for (i) the further investigation of the so far under-researched potentials and limitations of municipal food waste prevention as well as for (ii) local (network) activities which strengthen food waste prevention on the level of municipalities.

How many neurons are sufficient for perception of cortical activity?

Many theories of brain function propose that activity in sparse subsets of neurons underlies perception and action. To place a lower bound on the amount of neural activity that can be perceived, we used an all-optical approach to drive behaviour with targeted two-photon optogenetic activation of small ensembles of L2/3 pyramidal neurons in mouse barrel cortex while simultaneously recording local network activity with two-photon calcium imaging. By precisely titrating the number of neurons stimulated, we demonstrate that the lower bound for perception of cortical activity is ~14 pyramidal neurons. We find a steep sigmoidal relationship between the number of activated neurons and behaviour, saturating at only ~37 neurons, and show this relationship can shift with learning. Furthermore, activation of ensembles is balanced by inhibition of neighbouring neurons. This surprising perceptual sensitivity in the face of potent network suppression supports the sparse coding hypothesis, and suggests that cortical perception balances a trade-off between minimizing the impact of noise while efficiently detecting relevant signals.

Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus

Cell lineage in the adult hippocampus comprises multipotent and neuron-committed progenitors. In the present work, we fate-mapped neuronal progenitors using Dcx-CreERT2 and CAG-CAT-EGFP double-transgenic mice (cDCX/EGFP). We show that 3 days after tamoxifen-mediated recombination in cDCX/EGFP adult mice, GFP+ cells in the dentate gyrus (DG) co-expresses DCX and about 6% of these cells are proliferative neuronal progenitors. After 30 days, 20% of GFP+ generated from these progenitors differentiate into GFAP+ astrocytes. Unilateral intrahippocampal administration of the chemoconvulsants kainic acid (KA) or pilocarpine (PL) triggered epileptiform discharges and led to a significant increase in the number of GFP+ cells in both ipsi and contralateral DG. However, while PL favored the differentiation of neurons in both ipsi- and contralateral sides, KA stimulated neurogenesis only in the contralateral side. In the ipsilateral side, KA injection led to an unexpected increase of astrogliogenesis in the Dcx-lineage. We also observed a small number of GFP+/GFAP+ cells displaying radial-glia morphology ipsilaterally 3 days after KA administration, suggesting that some Dcx-progenitors could regress to a multipotent stage. The boosted neurogenesis and astrogliogenesis observed in the Dcx-lineage following chemoconvulsants administration correlated, respectively, with preservation or degeneration of the parvalbuminergic plexus in the DG. Increased inflammatory response, by contrast, was observed both in the DG showing increased neurogenesis or astrogliogenesis. Altogether, our data support the view that cell lineage progression in the adult hippocampus is not unidirectional and could be modulated by local network activity and GABA-mediated signaling.

Dynamics of multiple interacting excitatory and inhibitory populations with delays.

A network consisting of excitatory and inhibitory (EI) neurons is a canonical model for understanding local cortical network activity. In this study, we extended the local circuit model and investigated how its dynamical landscape can be enriched when it interacts with another excitatory (E) population with long transmission delays. Through analysis of a rate model and numerical simulations of a corresponding network of spiking neurons, we studied the transition from stationary to oscillatory states by analyzing the Hopf bifurcation structure in terms of two network parameters: (1) transmission delay between the EI subnetwork and the E population and (2) inhibitory couplings that induced oscillatory activity in the EI subnetwork. We found that the critical coupling strength can strongly modulate as a function of transmission delay, and consequently the stationary state can be interwoven intricately with the oscillatory state. Such a dynamical landscape gave rise to an isolated stationary state surrounded by multiple oscillatory states that generated different frequency modes, and cross-frequency coupling developed naturally at the bifurcation points. We identified the network motifs with short- and long-range inhibitory connections that underlie the emergence of oscillatory states with multiple frequencies. Thus, we provided a mechanistic explanation of how the transmission delay to and from the additional E population altered the dynamical landscape. In summary, our results demonstrated the potential role of long-range connections in shaping the network activity of local cortical circuits.

Ih, GIRK, and KCNQ/Kv7 channels differently modulate sharp wave - ripples in the dorsal and ventral hippocampus

Sharp waves and ripples (SPW-Rs) are endogenous transient patterns of hippocampus local network activity implicated in several functions including memory consolidation, and they are diversified between the dorsal and the ventral hippocampus. Ion channels in the neuronal membrane play important roles in cell and local network function. In this study, using transverse slices and field potential recordings from the CA1 field of rat hippocampus we show that GIRK and KCNQ2/3 potassium channels play a higher role in modulating SPW-Rs in the dorsal hippocampus, while Ih and other KCNQ (presumably KCNQ5) channels, contribute to shaping SPW-R activity more in the ventral than in dorsal hippocampus. Specifically, blockade of Ih channels by ZD 7288 reduced the rate of occurrence of SPW-Rs and increased the generation of SPW-Rs in the form of clusters in both hippocampal segments, while enhanced the amplitude of SPW-Rs only in the ventral hippocampus. Most effects of ZD 7288 appeared to be independent of NMDA receptors' activity. However, the effects of blockade of NMDA receptors depended on the functional state of Ih channels in both hippocampal segments. Blockade of GIRK channels by Tertiapin-Q increased the rate of occurrence of SPW-Rs only in the dorsal hippocampus and the probability of clusters in both segments of the hippocampus. Blockade of KCNQ2/3 channels by XE 991 increased the rate of occurrence of SPW-Rs and the probability of clusters in the dorsal hippocampus, and only reduced the clustered generation of SPW-Rs in the ventral hippocampus. The blocker of KCNQ1/2 channels, that also enhances KCNQ5 channels, UCL 2077, increased the probability of clusters and the power of the ripple oscillation in the ventral hippocampus only. These results suggest that GIRK, KCNQ and Ih channels represent a key mechanism for modulation of SPW-R activity which act differently in the dorsal and ventral hippocampus, fundamentally supporting functional diversification along the dorsal-ventral axis of the hippocampus.