In Drosophila , in vivo functional imaging studies revealed that associative memory formation is coupled to a cascade of neural plasticity events in distinct compartments of the mushroom body (MB). In-depth investigation of the circuit dynamics, however, will require an ex vivo model that faithfully mirrors these events to allow direct manipulations of circuit elements that are inaccessible in the intact fly. The current ex vivo models have been able to reproduce the fundamental plasticity of aversive short-term memory, a potentiation of the MB intrinsic neurons (Kenyon cells; KCs) responses after artificial learning ex vivo . However, this potentiation showed different localization and encoding properties from those reported in vivo and failed to generate the previously reported suppression plasticity in the mushroom body output neurons (MBONs). Here, we develop an ex vivo model using the female Drosophila brain that recapitulates behaviorally evoked plasticity in the KCs and MBONs. We demonstrate that th...

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (On-Off DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction (pDSGCs) in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize i...

In all cell types, endocytosed cargo is transported along a set of endosomal compartments, which are linked maturationally from early endosomes (EE) via late endosomes (LE) to lysosomes. Lysosomes are critical for degradation of proteins that enter through endocytic as well as autophagic pathways. Rab7 is the master regulator of early-to-late endosome maturation, motility, and fusion with lysosomes. We previously showed that most degradative lysosomes are localized in the soma and in the first 25 µm of the dendrite and that bulk degradation of dendritic membrane proteins occurs in/near the soma. Dendritic late endosomes therefore move retrogradely in a Rab7-dependent manner for fusion with somatic lysosomes. We now used cultured E18 rat hippocampal neurons of both sexes to determine which microtubule motor is responsible for degradative flux of late endosomes. Based on multiple approaches (inhibiting dynein/dynactin itself or inhibiting dynein recruitment to endosomes by expressing the C-terminus of the Ra...

Adult neurogenesis modifies hippocampal circuits and behavior but removing newborn neurons does not consistently alter spatial processing, a core function of the hippocampus. Additionally, little is known about sex differences in neurogenesis since few studies have compared males and females. Since adult-born neurons regulate the stress response, we hypothesized that spatial functions may be more prominent under aversive conditions, and may differ between males and females given sex differences in stress responding. We therefore trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. In the standard water maze, ablating neurogenesis did not alter spatial learning in either sex. However, in cold water, ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape the maze and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-...

Hippocampal seizures are a defining feature of mesial temporal lobe epilepsy. Area CA1 of the hippocampus is commonly implicated in the generation of seizures, which may occur due to the activity of endogenous cell populations or of inputs from other regions within the hippocampal formation. Simultaneously observing activity at the cellular and network scales in vivo remains challenging. Here, we present a novel technology for simultaneous electrophysiology and multicellular calcium imaging of CA1 pyramidal cells in mice enabled by a transparent graphene-based microelectrode array. We examine pyramidal cell firing at seizure onset, oscillatory coupling, and the dynamics of the seizure traveling wave as seizures evolve. Finally, we couple features derived from both modalities to predict the speed of the traveling wave using bootstrap aggregated regression trees. Analysis of the most important features in the regression trees suggests a transition among states in the evolution of hippocampal seizures. Signi...

Endosomal transport and positioning cooperate in the establishment of neuronal compartment architecture, dynamics and function, contributing to neuronal intracellular logistics. Furthermore, dysfunction of endo-lysosomal has been identified as a common mechanism in neurodegenerative diseases. Here, we analyzed endo-lysosomal transport when α-synuclein (α-syn) fibrillar polymorphs, ß-amyloid (Aß) fibrils and oligomers were externally applied on primary cultures of mouse cortical neurons. To measure this transport, we used a simple readout based on the spontaneous endocytosis in cultured neurons of fluorescent nanodiamonds, a perfectly stable nano-emitter, and the subsequent automatic extraction and quantification of their directed motions at high-throughput. α-syn fibrillar polymorphs, Aß fibrils and oligomers induce a two-fold decrease of the fraction of nanodiamonds transported along microtubules, while only slightly reducing their interaction with cortical neurons. This important decrease in moving endos...

Sensing the movement of fast objects within our visual environments is essential for controlling actions. It requires online estimation of motion direction and speed. We probed human speed representation using ocular tracking of stimuli of different statistics. First, we compared ocular responses to single drifting gratings with a given set of spatiotemporal frequencies to broadband Motion Clouds of matched mean frequencies. Motion energy distributions of gratings and clouds are point-like, and ellipses oriented along the constant speed axis, respectively. Sampling frequency space, Motion Clouds elicited stronger, less variable and speed-tuned responses. Drifting gratings yielded weaker and more frequency-tuned responses. Second, we measured responses to patterns made of two or three components covering a range of orientations within Fourier space. Early tracking initiation of the patterns was best predicted by a linear combination of components before nonlinear interactions emerged to shape later dynamics...

The neural underpinnings of humans’ ability to process faces and how it changes over typical development have been extensively studied using paradigms where face stimuli are oversimplified, isolated, and de-contextualized. The prevalence of this approach, however, has resulted in limited knowledge of face processing in ecologically valid situations, in which faces are accompanied by contextual information at multiple time scales. In the present study, we use a naturalistic movie paradigm to investigate how neuromagnetic activation and phase synchronization elicited by faces from movie scenes in humans differ between children and adults. We used MEG data from 22 adults (6 females, 3 left-handed, mean age 27.7±5.28 years old) and 20 children (7 females, 1 left-handed, mean age 9.5±1.52 years old) collected during movie viewing. We investigated neuromagnetic time-locked activation and phase synchronization elicited by movie scenes containing faces. Statistical differences between groups were tested using a mu...

The first evidence of local translation in the CNS appeared nearly 40 years ago, when electron microscopic studies showed polyribosomes localized to the base of dendritic spines. Since then, local translation has been established as an important regulatory mechanism for gene expression in polarized or functionally compartmentalized cells. While much attention has been placed on characterizing the local transcriptome and regulatory “grammar” directing mRNA localization in neurons and glia, less is understood about how these cells subsequently de-repress mRNA translation in their peripheral processes to produce a rapid translational response to stimuli. MicroRNA-mediated translation regulation offers a possible solution to this question. Not only do miRNAs provide the specificity needed for targeted gene regulation, but association and dynamic interactions between Argonaute (AGO) with sequence-specific RNA-binding proteins may provide a molecular switch to allow for de-repression of target mRNAs. Here, we re...

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, whereas higher-order areas are thought to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axodendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of male mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feed...