The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal ...axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In basic neuroscience research, data are often clustered or collected with repeated measures, hence correlated. The most widely used methods such as t test and ANOVA do not take data dependence into ...account and thus are often misused. This Primer introduces linear and generalized mixed-effects models that consider data dependence and provides clear instruction on how to recognize when they are needed and how to apply them. The appropriate use of mixed-effects models will help researchers improve their experimental design and will lead to data analyses with greater validity and higher reproducibility of the experimental findings.
In this Primer, Yu et al. introduce linear and generalized mixed-effects models for improved statistical analysis in neuroscience research and provide clear instruction on how to recognize when they are needed and how to apply them.
Circadian clocks regulate much of behavior and physiology, but the mechanisms by which they do so remain poorly understood. While cyclic gene expression is thought to underlie metabolic rhythms, ...little is known about cycles in cellular physiology. We found that Drosophila insulin-producing cells (IPCs), which are located in the pars intercerebralis and lack an autonomous circadian clock, are functionally connected to the central circadian clock circuit via DN1 neurons. Insulin mediates circadian output by regulating the rhythmic expression of a metabolic gene (sxe2) in the fat body. Patch clamp electrophysiology reveals that IPCs display circadian clock-regulated daily rhythms in firing event frequency and bursting proportion under light:dark conditions. The activity of IPCs and the rhythmic expression of sxe2 are additionally regulated by feeding, as demonstrated by night feeding-induced changes in IPC firing characteristics and sxe2 levels in the fat body. These findings indicate circuit-level regulation of metabolism by clock cells in Drosophila and support a role for the pars intercerebralis in integrating circadian control of behavior and physiology.
Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult ...brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore,
calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.
Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases
neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.
Animals partition their daily activity rhythms through their internal circadian clocks, which are synchronized by oscillating day-night cycles of light. The fruitfly Drosophila melanogaster senses ...day-night cycles in part through rhodopsin-dependent light reception in the compound eye and photoreceptor cells in the Hofbauer-Buchner eyelet. A more noteworthy light entrainment pathway is mediated by central pacemaker neurons in the brain. The Drosophila circadian clock is extremely sensitive to light. However, the only known light sensor in pacemaker neurons, the flavoprotein cryptochrome (Cry), responds only to high levels of light in vitro. These observations indicate that there is an additional light-sensing pathway in fly pacemaker neurons. Here we describe a previously uncharacterized rhodopsin, Rh7, which contributes to circadian light entrainment by circadian pacemaker neurons in the brain. The pacemaker neurons respond to violet light, and this response depends on Rh7. Loss of either cry or rh7 caused minor defects in photoentrainment, whereas loss of both caused profound impairment. The circadian photoresponse to constant light was impaired in rh7 mutant flies, especially under dim light. The demonstration that Rh7 functions in circadian pacemaker neurons represents, to our knowledge, the first role for an opsin in the central brain.
Viral tracers are important tools for neuroanatomical mapping and genetic payload delivery. Genetically modified viruses allow for cell-type-specific targeting and overcome many limitations of ...non-viral tracers. Here, we summarize the viruses that have been developed for neural circuit mapping, and we provide a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses. We also discuss and highlight key technical and conceptual considerations for developing new safer and more effective anterograde trans-synaptic viral vectors for neural circuit analysis in multiple species.
Xu et al. review the viruses that have been used for neural circuit mapping and provide a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms ...in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at two different ages (3–4 vs. 10–11 months old). We quantitatively mapped the connectivity strengths of neural circuit inputs to hippocampal CA1 excitatory neurons from brain regions including hippocampal subregions, medial septum, subiculum and entorhinal cortex, comparing different age groups and genotypes. We focused on hippocampal CA1 because of its clear relationship with learning and memory and that the hippocampal formation shows clear neuropathological changes in human AD. Our results reveal alterations in circuit connectivity of hippocampal CA1 in AD model mice. Overall, we find weaker extrinsic CA1 input connectivity strengths in AD model mice compared with control mice, including sex differences of reduced subiculum to CA1 inputs in aged female AD mice compared with aged male AD mice. Unexpectedly, we find a connectivity pattern shift with an increased proportion of inputs from the CA3 region to CA1 excitatory neurons when comparing young and old AD model mice, as well as old wild-type mice and old AD model mice. These unexpected shifts in CA3-CA1 input proportions in this AD mouse model suggest the possibility that compensatory circuit increases may occur in response to connectivity losses in other parts of the hippocampal circuits. We expect that this work provides new insights into the neural circuit mechanisms of AD pathogenesis.
•Our study is the first to apply monosynaptic rabies tracing to an AD mouse model.•AD mice exhibit age-progressive and reduced hippocampal CA1 connectivity.•CA1 excitatory neuron inputs shift with hippocampal regions in AD mice.•Aged female AD mice show significantly reduced subiculum to CA1 projections.
The study of Alzheimer's Disease (AD) has traditionally focused on neuropathological mechanisms that has guided therapies that attenuate neuropathological features. A new direction is emerging in AD ...research that focuses on the progressive loss of cognitive function due to disrupted neural circuit mechanisms. Evidence from humans and animal models of AD show that dysregulated circuits initiate a cascade of pathological events that culminate in functional loss of learning, memory, and other aspects of cognition. Recent progress in single-cell, spatial, and circuit omics informs this circuit-focused approach by determining the identities, locations, and circuitry of the specific cells affected by AD. Recently developed neuroscience tools allow for precise access to cell type-specific circuitry so that their functional roles in AD-related cognitive deficits and disease progression can be tested. An integrated systems-level understanding of AD-associated neural circuit mechanisms requires new multimodal and multi-scale interrogations that longitudinally measure and/or manipulate the ensemble properties of specific molecularly-defined neuron populations first susceptible to AD. These newly developed technological and conceptual advances present new opportunities for studying and treating circuits vulnerable in AD and represent the beginning of a new era for circuit-based AD research.
Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular ...deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period downregulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular, and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity.
•NRG1/ErbB4 signaling shows developmental and experience-dependent regulation•NRG1 restores excitation to deprived PV neurons to enhance cortical inhibition•NRG1/ErbB4 signaling in PV neurons is coupled to AMPA receptor response modulation•NRG1 treatment suppresses critical period ocular dominance plasticity in vivo
Sun et al. finds that NRG1/ErbB4 signaling regulates the initiation of critical period visual cortical plasticity by rapidly controlling excitatory synaptic inputs onto PV neurons and thus PV-cell-mediated cortical inhibition in response to visual deprivation.
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