In all cell types, endocytosed cargo is transported along a set of endosomal compartments, which are linked maturationally from early endosomes (EEs) via late endosomes (LEs) 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 ...

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not thet...

Hippocampal place cells form a map of an animal’s environment. Changes in the hippocampal map can be brought about in a number of ways, including changes to the environment, task, internal state of the subject, and the passage of time. These changes in the hippocampal map have been called “remapping”. In this study, we examine remapping during repeated exposure to the same environment. Different animals can have different remapping responses to the same changes. This variability across animals in remapping behavior is not well understood. In this work, we analyzed electrophysiological recordings from the CA3 region of the hippocampus performed by Alme et al. (2014), in which five male rats were exposed to 11 different environments, including a variety of repetitions of those environments. To compare the hippocampal maps between two experiences, we computed average rate map correlation coefficients. We found changes in the hippocampal maps between different sessions in the same environment. These changes co...

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus–norepinephrine (LC–NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC–NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurren...

Sensory evidence accumulation is considered a hallmark of decision-making in noisy environments. Integration of sensory inputs has been traditionally studied using passive stimuli, segregating perception from action. Lessons learned from this approach, however, may not generalize to ethological behaviors like navigation, where there is an active interplay between perception and action. We designed a sensory-based sequential decision task in virtual reality in which humans and monkeys navigated to a memorized location by integrating optic flow generated by their own joystick movements. A major challenge in such closed-loop tasks is that subjects’ actions will determine future sensory input, causing ambiguity about whether they rely on sensory input rather than expectations based solely on a learned model of the dynamics. To test whether subjects integrated optic flow over time, we used three independent experimental manipulations: unpredictable optic flow perturbations, which pushed subjects off their traje...

The Mauthner cells are a pair of large reticulospinal neurons that organize sensory-evoked tail flip responses in fishes. An identifiable group of auditory “mixed” (electrical and chemical) synaptic contacts known as “Large Myelinated Club Endings” on these cells have provided a valuable model for the study of synaptic transmission in the vertebrate brain. While most of studies were performed in adult fish, we describe here methods that make possible recording synaptic transmission from these contacts in developing zebrafish, a genetically tractable vertebrate species which is uniquely amenable for combining synaptic physiology with live imaging and behavioral analysis. Significance statement An identifiable type of “mixed” synaptic contacts on the fish Mauthner cells provide a valuable model for the study of synaptic transmission in the vertebrate brain. We describe here methods to record synaptic potentials from these contacts in developing zebrafish. The approach makes possible to explore the molecul...

Intracranial neurophysiological recordings require chronic implants to provide transcranial access to the brain. Especially in larger animals, which participate in experiments over extended periods of time, implants should match the skull curvature to promote osseointegration and avoid tissue and bacterial ingress over time. Proposed CAD methods for designing implants to date have focused on naïve animals with continuous and even skull surfaces and calculate Boolean differences between implant and skull surface to fit the implant to the skull curvature. However, custom-fitting by calculating the difference fails, if a discontinuous skull surface needs to be matched. Also, the difference method does not allow designs with constant material thickness along the skull curvature, e.g. to allow fixed screw lengths. We present a universal step-by-step guide for custom-fitting implants which overcomes these limitations. It is suited for unusual skull conditions, like surface discontinuities or irregularities and i...

People with photosensitive epilepsy (PSE) are prone to seizures elicited by visual stimuli. The possibility of inducing epileptiform activity in a reliable way makes PSE a useful model to understand epilepsy, with potential applications for the development of new diagnostic methods and new treatments for epilepsy. A relationship has been demonstrated between PSE and both occipital and more widespread cortical hyperexcitability using various types of stimulation. Here we aimed to test whether hyperexcitability could be inferred from resting interictal electroencephalographic (EEG) data without stimulation. We considered a cohort of 46 individuals with idiopathic generalised epilepsy (IGE) that underwent EEG during intermittent photic stimulation (IPS): 26 had a photoparoxysmal response (PPR), the PPR group, and 20 did not, the non-PPR group. For each individual, we computed functional networks from the resting EEG data prior to stimulation. We then placed a computer model of ictogenicity into the networks a...

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats’ oromotor and somatic reactions to intraoral infusions of sucrose were periodically assessed over 45 minutes following Lithium Chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl inject...

Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the TARDBP gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TARDBP mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA processing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Here, we examined global RNA processing in forebrain cortical neurons derived from human induced pluripotent stem cells (iPSCs) with a pathogenic TARDBP mutation encoding the TDP-43K263E protein. In neurons expressing mutant TDP-43, we detected disrupted RNA regulation, including global changes in gene expression, missplicing, and aberrant polyadenylation, all of which were highly similar to those induced by TDP-43 knockdown. This mutation-induced TDP-43 LOF w...