Silencing CA1 pyramidal cells output reveals the role of feedback inhibition in hippocampal oscillations.

The precise temporal coordination of neural activity is crucial for brain function. In the hippocampus, this precision is reflected in the oscillatory rhythms observed in CA1. While it is known that a balance between excitatory and inhibitory activity is necessary to generate and maintain these oscillations, the differential contribution of feedforward and feedback inhibition remains ambiguous. Here we use conditional genetics to chronically silence CA1 pyramidal cell transmission, ablating the ability of these neurons to recruit feedback inhibition in the local circuit, while recording physiological activity in mice. We find that this intervention leads to local pathophysiological events, with ripple amplitude and intrinsic frequency becoming significantly larger and spatially triggered local population spikes locked to the trough of the theta oscillation appearing during movement. These phenotypes demonstrate that feedback inhibition is crucial in maintaining local sparsity of activation and reveal the key role of lateral inhibition in CA1 in shaping circuit function.

Silencing dentate newborn neurons alters excitatory/inhibitory balance and impairs behavioral inhibition and flexibility.

Adult neurogenesis confers the hippocampus with unparalleled neural plasticity, essential for intricate cognitive functions. The specific influence of sparse newborn neurons (NBNs) in modulating neural activities and subsequently steering behavior, however, remains obscure. Using an engineered NBN-tetanus toxin mouse model (NBN-TeTX), we noninvasively silenced NBNs, elucidating their crucial role in impulse inhibition and cognitive flexibility as evidenced through Morris water maze reversal learning and Go/Nogo task in operant learning. Task-based functional MRI (tb-fMRI) paired with operant learning revealed dorsal hippocampal hyperactivation during the Nogo task in male NBN-TeTX mice, suggesting that hippocampal hyperexcitability might underlie the observed behavioral deficits. Additionally, resting-state fMRI (rs-fMRI) exhibited enhanced functional connectivity between the dorsal and ventral dentate gyrus following NBN silencing. Further investigations into the activities of PV+ interneurons and mossy cells highlighted the indispensability of NBNs in maintaining the hippocampal excitation/inhibition balance. Our findings emphasize that the neural plasticity driven by NBNs extensively modulates the hippocampus, sculpting inhibitory control and cognitive flexibility.

From synapses to circuits: What mouse models have taught us about how autism spectrum disorder impacts hippocampal function.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that impacts a variety of cognitive and behavioral domains. While a genetic component of ASD has been well-established, none of the numerous syndromic genes identified in humans accounts for more than 1% of the clinical patients. Due to this large number of target genes, numerous mouse models of the disorder have been generated. However, the focus on distinct brain circuits, behavioral phenotypes and diverse experimental approaches has made it difficult to synthesize the overwhelming number of model animal studies into concrete throughlines that connect the data across levels of investigation. Here we chose to focus on one circuit, the hippocampus, and one hypothesis, a shift in excitatory/inhibitory balance, to examine, from the level of the tripartite synapse up to the level of in vivo circuit activity, the key commonalities across disparate models that can illustrate a path towards a better mechanistic understanding of ASD's impact on hippocampal circuit function.

Understanding petroleum vapor fate and transport through high resolution analysis of two distinct vapor plumes.

No field study has provided a detailed characterization of the molecular composition and spatial distribution of a vadose zone plume of petroleum volatile organic compounds (VOCs), which is critical to improve the current understanding of petroleum VOC transport and fate. This is study reports a high-resolution analysis of two distinct vapor plumes emanating from two different light non-aqueous phase liquid (LNAPL) sources (an aliphatic-rich LNAPL for Zone #1vs an aromatic-rich LNAPL for Zone #2) at a large petrochemical site. Although deep soil vapor signatures were similar to the source zone LNAPL signatures, the composition of the shallow soil vapors reflected preferential attenuation of certain hydrocarbons over others during upward transport in the vadose zone. Between deeper and shallower soil gas samples, attenuation of aromatics was observed under all conditions, but important differences were observed in attenuation to aliphatic compound classes. Attenuation of all aliphatic compounds was observed under aerobic conditions but little attenuation of any aliphatics was observed under anoxic conditions without methane. In contrast, under methanogenic conditions, paraffins attenuated more than isoparaffins and naphthenes. These results suggest that isoparafins and naphthenes may present more of a vapor intrusion risk than benzene or other aromatic hydrocarbons commonly considered to be petroleum vapor intrusion risk drivers. While the overall vapor composition changed significantly within the vadose zone, diagnostic ratios of relatively recalcitrant alkylcyclopentanes were preserved in shallow soil vapor samples. These alkylcyclopentanes may be useful for distinguishing between petroleum vapor intrusion and other sources of petroleum VOCs detected in indoor air.

A signal EMerGes from the noise.

In this issue of Cell Reports Methods, Osanai et al. report an innovative approach to extract an electromyography (EMG) signal from multi-channel local field potential (LFP) recordings using independent component analysis (ICA). This ICA-based approach offers precise and stable long-term behavioral assessment, eliminating the need for direct muscular recordings.

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development.

The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

Behavioral status modulates CA2 influence on hippocampal network dynamics.

Dynamic interactions between the subregions of the hippocampus are required for the encoding and consolidation of memory. While the interplay and contributions of the CA1 and CA3 regions are well understood, we continue to learn more about how CA2 differentially contributes to the organization of network function. For example, CA2 place cells have been reported to be less spatially tuned during exploration, but uniquely capable of coding place while an animal stops. Here we applied chemogenetics to transiently silence CA2 pyramidal cells and found that CA2 influences hippocampal dynamics in a state-dependent manner. We find that during rest, CA2 inhibition reduces synchronization across regions (CA1, CA2, CA3) and frequency bands (low-gamma- and ripple-band). Moreover, during new learning CA1 place field formation is slower in the absence of CA2 transmission and during pausing, CA1 pyramidal cells are less excitable without CA2 drive. On the network level, a novel convolutional neural network (SpikeDecoder) was employed to show subregion and state-dependent changes in spatial coding that agree with our observations on the single cell level. Together these data suggest additional novel roles for CA2 in governing and differentiating hippocampal dynamics under discrete behavioral states.

Role of Calcr expressing neurons in the medial amygdala in social contact among females.

Social animals become stressed upon social isolation, proactively engaging in affiliative contacts among conspecifics after resocialization. We have previously reported that calcitonin receptor (Calcr) expressing neurons in the central part of the medial preoptic area (cMPOA) mediate contact-seeking behaviors in female mice. Calcr neurons in the posterodorsal part of the medial amygdala (MeApd) are also activated by resocialization, however their role in social affiliation is still unclear. Here we first investigated the functional characteristics of MeApd Calcr + cells; these neurons are GABAergic and show female-biased Calcr expression. Next, using an adeno-associated virus vector expressing a short hairpin RNA targeting Calcr we aimed to identify its molecular role in the MeApd. Inhibiting Calcr expression in the MeApd increased social contacts during resocialization without affecting locomotor activity, suggesting that the endogenous Calcr signaling in the MeApd suppresses social contacts. These results demonstrate the distinct roles of Calcr in the cMPOA and MeApd for regulating social affiliation.

The expanded circuitry of hippocampal ripples and replay.

The place cells and well-defined oscillatory population rhythms of the rodent hippocampus have served as a powerful model system in linking cells and circuits to memory function. While the initial three decades of place cell research primarily focused on the activity of neurons during exploration, the last twenty-five years have seen growing interest in the physiology of the hippocampus at rest. During slow-wave sleep and quiet wakefulness the hippocampus exhibits sharp-wave ripples (SWRs), short high-frequency, high-amplitude oscillations, that organize the reactivation or 'replay' of sequences of place cells, and interventions that disrupt SWRs impair learning. While the canonical model of SWRs generation have emphasized CA3 input to CA1 as the source of excitatory drive, recent work suggests there are multiple circuits, including the CA2 region, that can both influence, generate and organize SWRs, both from the oscillatory and information content perspectives in a task and state-dependent manner. This extended circuitry and its function must be considered for a true understanding of the role of the hippocampus in off-line processes such as planning and consolidation.

Natural source zone depletion (NSZD) insights from over 15 years of research and measurements: A multi-site study.

Site-average Natural Source Zone Depletion (NSZD) rates measured from 40 petroleum light non-aqueous phase liquid (LNAPL) source zone sites were compiled from researchers, project reports, and scientific papers. At each site, the following data were compiled: i) general site location; ii) LNAPL fuel type; iii) measurement method, number of locations, and number of measurements per location; and iv) calculated site-average NSZD rate in liters per hectare per year (L/ha/yr) per site and the associated measurement method (i.e., Gradient Method, Carbon Traps, Dynamic Closed Chamber (DCC), or Thermal Monitoring). The resulting dataset showed site-average NSZD rates that ranged from 650 to 152,000 L/ha/yr (70 to 16,250 gallons per acre per year (gal/acre/yr)), with a median value of 9,540 L/ha/yr (1,020 gal/acre/yr). The median site-average NSZD rate by type of fuel spill did not show a statistically significant difference between fuel types. When comparing the different NSZD measurement methods applied to the same sites, the site-average NSZD rates differed by up to 4.8 times (i.e., ratio of faster rate to slower rate), with a median difference of 2.1 times. No clear bias was observed between NSZD rate measurement methods. At four sites with calculations of NSZD rates by season, NSZD rates were typically higher during summer and fall compared to winter and spring. For these sites, Q10 values (a measure of the increase in NSZD rate associated with a 10 °C increase in temperature) ranged from 0.8 to 15.1, with a median of 2.2. The implications of this study suggest that increasing mean annual soil temperature at a site using engineered methods could potentially increase the biodegradation rate (e.g., an increase of 10 °C could double the NSZD rate). Finally, for five sites with site-average NSZD rates for multiple years, average NSZD rates varied by 1.1 to 4.9 times across years. Overall, the evaluation of NSZD rates measured at 40 LNAPL sites suggests that measurable NSZD occurs across a broad range of LNAPL sites. Although NSZD rates vary across sites, fuel type is not the primary factor explaining observed differences in rates.

Author response to technical commentary: Direct aerobic NSZD of a basalt vadose zone LNAPL source in Hawaii, McHugh et al., JCH #235 (2020).

Our Paper uses two independent methods (carbon dioxide flux and heat flux) to measure the rates of natural source zone depletion (NSZD) at a petroleum release site in Hawaii. The two methods yielded estimates of the NSZD rate that agreed within a factor of 2. We disagree with the technical commentors (Beckett et al., 2022). Specifically, the available data indicate that the observed NSZD is not occurring through a two-stage process of methane generation at the water table followed by methane oxidation in the vadose zone; rather direct aerobic oxidation of LNAPL in the vadose zone is the simplest and most likely explanation for the observed heat generation. In addition, the agreement between the two independent NSZD rate measurement methods and the temporal consistency in the measured heat flux across two field events provides confidence that the NSZD rates presented in the paper are not greatly over or under-estimated.

Alterations in a cross-hemispheric circuit associates with novelty discrimination deficits in mouse models of neurodegeneration.

A major pathological hallmark of neurodegenerative diseases, including Alzheimer's, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration.

A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model.

Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, from brain inflammation to disturbed innate/adaptive immune in the periphery, are frequently observed in patients with autism; however, the intrinsic mechanisms behind them remain elusive. We hypothesize a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism. It is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development. Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain. We further confirm that dysregulated immune profiles are associated with specific microbiota composition, which may serve as a biomarker to identify autism of immune-dysregulated subtypes. Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

Behavioral and Cellular Tagging in Young and in Early Cognitive Aging.

The ability to maintain relevant information on a daily basis is negatively impacted by aging. However, the neuronal mechanism manifesting memory persistence in young animals and memory decline in early aging is not fully understood. A novel event, when introduced around encoding of an everyday memory task, can facilitate memory persistence in young age but not in early aging. Here, we investigated in male rats how sub-regions of the hippocampus are involved in memory representation in behavioral tagging and how early aging affects such representation by combining behavioral training in appetitive delayed-matching-to-place tasks with the "cellular compartment analysis of temporal activity by fluorescence in situ hybridization" technique. We show that neuronal assemblies activated by memory encoding were also partially activated by novelty, particularly in the distal CA1 and proximal CA3 subregions in young male rats. In early aging, both encoding- and novelty-triggered neuronal populations were significantly reduced with a more profound effect in encoding neurons. Thus, memory persistence through novelty facilitation engages overlapping hippocampal assemblies as a key cellular signature, and cognitive aging is associated with underlying reduction in neuronal activation.

Amylin-Calcitonin receptor signaling in the medial preoptic area mediates affiliative social behaviors in female mice.

Social animals actively engage in contact with conspecifics and experience stress upon isolation. However, the neural mechanisms coordinating the sensing and seeking of social contacts are unclear. Here we report that amylin-calcitonin receptor (Calcr) signaling in the medial preoptic area (MPOA) mediates affiliative social contacts among adult female mice. Isolation of females from free social interactions first induces active contact-seeking, then depressive-like behavior, concurrent with a loss of Amylin mRNA expression in the MPOA. Reunion with peers induces physical contacts, activates both amylin- and Calcr-expressing neurons, and leads to a recovery of Amylin mRNA expression. Chemogenetic activation of amylin neurons increases and molecular knockdown of either amylin or Calcr attenuates contact-seeking behavior, respectively. Our data provide evidence in support of a previously postulated origin of social affiliation in mammals.

K+ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake.

Glutamatergic transmission prompts K+ efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K+ elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astrocytic glutamate transporter current (IGluT ), whereas blocking astrocytic K+ channels prevents the duration increase only. Glutamate spot-uncaging reveals that astrocyte depolarization, rather than extracellular K+ rises per se, is required to reduce the amplitude and duration of IGluT . Biophysical simulations confirm that local transient elevations of extracellular K+ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K+ efflux to enhanced extrasynaptic glutamate signaling. Thus, repetitive glutamatergic transmission triggers a feedback loop in which postsynaptic K+ efflux can transiently facilitate presynaptic release while reducing local glutamate uptake.

The impact of stress on the hippocampal spatial code.

Hippocampal function is severely compromised by prolonged, uncontrollable stress. However, how stress alters neural representations of our surroundings and events that occur within them remains less clear. We review hippocampal place cell studies that examine how spatial coding is affected by acute and chronic stress, as well as by stress accompanying fear conditioning. Emerging data suggest that chronic stress disrupts the acuity and specificity of CA1 spatial coding, both in familiar and novel contexts, and alters hippocampal oscillations. By contrast, acute stress may have a facilitatory impact on spatial representations. These findings encourage a fresh look at the documented stress-induced changes in hippocampal anatomy and in vitro excitability, and offer a new perspective on the links between stress and memory.