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-...

A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences are used to compute spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) due to an inbred mutation in the Cadherin 23 gene ( Cdh23) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice. Here we show that 2-4-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation of auditory space in ...

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...

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...

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...

Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both non-glutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for regulation of glutamate signaling, and therefore modulates the activity of various brain microcircuits. However, little is known on how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we employed VGLUT3 constitutive knockout (VGLUT3–/–) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors, mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in levels of ionotropic NMDARs glutamate receptors were observed in the cerebral cortex of VGLUT3–/– mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopamine...

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKM ζ . However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse specificity. In this paper we address the issue of synapse specificity during memory maintenance. Assuming that the long-term maintenance of synaptic plasticity is accomplished by a molecular switch, we carry out analytical calculations and perform simulations using the reaction-diffusion package in NEURON to determine the limits of synapse specificity during maintenance. Moreover, we explore the effects of the diffusion and degradation rates of proteins and of the geometrical characteristics of dendritic spines on synapse specificity. We conclude ...