Hippocampal CA3 is traditionally conceptualized as a brain region within a unidirectional feedforward trisynaptic pathway that links major hippocampal subregions. Recent genomic and viral tracing ...studies indicate that the anatomical connectivity of CA3 and the trisynaptic pathway is more complex than initially expected and suggests that there may be cell type–specific input gradients throughout the three‐dimensional hippocampal structure. In several recent studies using multiple viral tracing approaches, we describe subdivisions of the subiculum complex and ventral hippocampal CA1 that show significant back projections to CA1 and CA3 excitatory neurons. These novel connections form “noncanonical” circuits that run in the opposite direction relative to the well‐characterized feedforward pathway. Diverse subtypes of GABAergic inhibitory neurons participate within the trisynaptic pathway. In the present study, we have applied monosynaptic retrograde viral tracing to examine noncanonical synaptic inputs from CA1 and subicular complex to the inhibitory neuron in hippocampal CA3. We quantitatively mapped synaptic inputs to CA3 inhibitory neurons to understand how they are connected within and beyond the hippocampus formation. Major brain regions that provide typical inputs to CA3 inhibitory neurons include the medial septum, the dentate gyrus, the entorhinal cortex, and CA3. Noncanonical inputs from ventral CA1 and subicular complex to CA3 inhibitory neurons follow a proximodistal topographic gradient with regard to CA3 subregions. We find novel noncanonical circuit connections between inhibitory CA3 neurons and ventral CA1, subiculum complex, and other brain regions. These results provide a new anatomical connectivity basis to further study the function of CA3 inhibitory neurons.
Lin et al. applied monosynaptic retrograde viral tracing to examine both typical and noncanonical circuit inputs to CA3 inhibitory neurons in the mouse to understand how they are connected within and beyond the hippocampal formation. Noncanonical inputs from ventral CA1 and the subicular complex to dorsal CA3 inhibitory neurons follow a proximodistal topographic gradient relative to CA3 subregions. This work provides a new anatomical connectivity basis for further studying the function of CA3 inhibitory neurons.
Daily rhythms in Drosophila under semi-natural conditions (or SN) have received much recent attention. One of the striking differences in the behaviour of wild type flies under SN is the presence of ...an additional peak of activity in the middle of the day. This is referred to as the afternoon peak (A-peak) and is absent under standard laboratory regimes using gated light and temperature cues. Although previous reports identified the physical factors that contribute towards the A-peak there is no evidence for underlying molecular mechanisms or pathways that control A-peak. We report that the A-peak is mediated by thermosensitive dTRPA1 (drosophila Transient Receptor Potential- A1) ion channels as this peak is absent in dTRPA1 null mutants. Further, when natural cycles of light and temperature are simulated in the lab, we find that the amplitude of the A-peak is dTRPA1-dependent. Although a few circadian neurons express dTRPA1, we show that modulation of A-peak is primarily influenced by non-CRY dTRPA1 expressing neurons. Hence, we propose that A-peak of activity observed under SN is a temperature sensitive response in flies that is elicited through dTRPA1 receptor signalling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Subanesthetic ketamine evokes rapid and long-lasting antidepressant effects in human patients. The mechanism for ketamine’s effects remains elusive, but ketamine may broadly modulate brain plasticity ...processes. We show that single-dose ketamine reactivates adult mouse visual cortical plasticity and promotes functional recovery of visual acuity defects from amblyopia. Ketamine specifically induces downregulation of neuregulin-1 (NRG1) expression in parvalbumin-expressing (PV) inhibitory neurons in mouse visual cortex. NRG1 downregulation in PV neurons co-tracks both the fast onset and sustained decreases in synaptic inhibition to excitatory neurons, along with reduced synaptic excitation to PV neurons in vitro and in vivo following a single ketamine treatment. These effects are blocked by exogenous NRG1 as well as PV targeted receptor knockout. Thus, ketamine reactivation of adult visual cortical plasticity is mediated through rapid and sustained cortical disinhibition via downregulation of PV-specific NRG1 signaling. Our findings reveal the neural plasticity-based mechanism for ketamine-mediated functional recovery from adult amblyopia.
•Disinhibition of excitatory cells by ketamine occurs in a fast and sustained manner•Ketamine evokes NRG1 downregulation and excitatory input loss in PV cells•Ketamine induced plasticity is blocked by exogenous NRG1 or its receptor knockout•PV inhibitory cells are the initial functional locus underlying ketamine’s effects
Grieco et al. find that subanesthetic ketamine downregulates NRG1 expression in PV inhibitory cells, resulting in sustained cortical disinhibition to enhance cortical plasticity in adult visual cortex. Their work establishes the neural plasticity-based mechanism for ketamine-mediated functional recovery from amblyopia.
The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we ...mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.
Experience‐dependent critical period (CP) plasticity has been extensively studied in the visual cortex. Monocular deprivation during the CP affects ocular dominance, limits visual performance, and ...contributes to the pathological etiology of amblyopia. Neuregulin‐1 (NRG1) signaling through its tyrosine kinase receptor ErbB4 is essential for the normal development of the nervous system and has been linked to neuropsychiatric disorders such as schizophrenia. We discovered recently that NRG1/ErbB4 signaling in PV neurons is critical for the initiation of CP visual cortical plasticity by controlling excitatory synaptic inputs onto PV neurons and thus PV‐cell mediated cortical inhibition that occurs following visual deprivation. Building on this discovery, we review the existing literature of neuregulin signaling in developing and adult cortex and address the implication of NRG/ErbB4 signaling in visual cortical plasticity at the cellular and circuit levels. NRG‐directed research may lead to therapeutic approaches to reactivate plasticity in the adult cortex.
This image is associated with Figure 2 in Grieco et al. in this issue. It is an artistic rendition of their image data illustrating enhanced local excitatory inputs to monocularly deprived PV neurons (white circles) with bath applied NRG1. The eye‐like overlay in black conveys that therapeutic intervention of NRG1/ErbB4 signaling can be developed to help treat critical period‐relevant disorders such as amblyopia. The review article of Grieco et al. addresses a novel and critical role of NRG1/ErbB4 in regulation of visual cortical critical period plasticity.
Significance CRYPTOCHROMES (CRYs) are blue light photoreceptors that mediate phototransduction in brain arousal neurons, as well as circadian light entrainment in Drosophila fruit flies. We describe ...how light-activated Drosophila CRY couples to membrane depolarization and increased action potential firing rate in large ventral lateral arousal neurons. Pharmacological treatments that specifically disrupt the CRY redox-sensitive flavin chromophore or block voltage-gated K ⁺ channels abolish the light response. Correspondingly, we find that the Kvβ channel subunit Hyperkinetic with a well conserved redox sensor domain links light-evoked redox changes in CRY to rapid changes in membrane electrical potential.
Blue light activation of the photoreceptor CRYPTOCHROME (CRY) evokes rapid depolarization and increased action potential firing in a subset of circadian and arousal neurons in Drosophila melanogaster . Here we show that acute arousal behavioral responses to blue light significantly differ in mutants lacking CRY, as well as mutants with disrupted opsin-based phototransduction. Light-activated CRY couples to membrane depolarization via a well conserved redox sensor of the voltage-gated potassium (K ⁺) channel β-subunit (Kvβ) Hyperkinetic (Hk). The neuronal light response is almost completely absent in hk ⁻/⁻ mutants, but is functionally rescued by genetically targeted neuronal expression of WT Hk, but not by Hk point mutations that disable Hk redox sensor function. Multiple K ⁺ channel α-subunits that coassemble with Hk, including Shaker, Ether-a-go-go, and Ether-a-go-go–related gene, are ion conducting channels for CRY/Hk-coupled light response. Light activation of CRY is transduced to membrane depolarization, increased firing rate, and acute behavioral responses by the Kvβ subunit redox sensor.
Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is ...biased by inputs from CA1 inhibitory neurons and the visual cortex, but lacks input from the entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target the perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. Our findings also implicate this circuitry in the formation of complex spatial representations and learning of object-place associations.
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