Learning to solve a new problem involves identifying the operating rules, which can be accelerated if known rules generalize in the new context. We ask how prior experience affects learning a new rule that is distinct from known rules. We examined how rats learned a new spatial navigation task after having previously learned tasks with different navigation rules. The new task differed from the previous tasks in spatial layout and navigation rule. We found that experience history did not impact overall performance. However, by examining navigation choice sequences in the new task, we found experience-dependent differences in exploration patterns during early stages of learning, as well as differences in the types of errors made during stable performance. The differences were consistent with the animals adopting experience-dependent memory strategies to discover and implement the new rule. Our results indicate prior experience shapes the strategies for solving novel problems, and the impact of prior experien...

Chemotherapy-related cognitive impairments (CRCIs) encompass cognitive deficits in memory, attention, and executive function that arise during and following chemotherapy. CRCI symptoms are predominantly reported by female cancer patients but also occur in males. These impairments may involve reduced estradiol levels, which then increases vulnerability to the impact of tumors and chemotherapy on cognition. This study utilized the MMTV-PyVT mouse model of breast cancer to test the hypothesis that impaired ovarian function and associated estradiol levels play a critical role in CRCI susceptibility. Mice were either ovariectomized (OVX) or underwent sham surgery. The OVX group then received supplemental estradiol (E2) ad libitum in the drinking water to maintain physiological hormone levels. After tumor development, mice were trained in the Morris water maze to assess spatial memory, and subsequently, they received weekly injections of either saline or a combination of cyclophosphamide (CYP; 66.7 mg/kg, i.v.) ...

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in sepsis-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood–brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammation. In the acute phase, we identified novel molecular (e.g., upregulation of plasmalemma...

There is experimental evidence of varying correlation among the elements of the neuromuscular system over the course of the reach-and-grasp task. The aim of this study was to investigate if modifications in correlations and clustering can be detected in the local field potential (LFP) recordings of the motor cortex during the task. To this end, we analyzed the LFP recordings from a previously published study on monkeys that performed a reach-and-grasp task for targets with a vertical or horizontal orientation. LFP signals were recorded from the motor and premotor cortex of macaque monkeys as they performed the task. We found very robust changes in the correlations of the multielectrode LFP recordings that corresponded to task epochs. Mean LFP correlation increased significantly during reach and then decreased during grasp. This pattern was very robust for both left and right arm reaches irrespective of target orientation. A hierarchical cluster analysis also demonstrated similar changes. In focusing on cor...

Retinitis pigmentosa (RP) is a family of genetically heterogeneous diseases still without a cure. Despite the causative genetic mutation typically not expressed in cone photoreceptors, these cells inevitably degenerate following the primary death of rods, causing blindness. The reasons for the “bystander” degeneration of cones are presently unknown but decrement of survival factors, oxidative stress, and inflammation all play a role. Targeting these generalized biological processes represents a strategy to develop mutation-agnostic therapies for saving vision in large populations of RP individuals. A classical method to support neuronal survival is by employing neurotrophic factors, such as NGF. This study uses painless human NGF (hNGFp), a TrkA receptor-biased variant of the native molecule with lower affinity for nociceptors and limited activity as a pain inducer; the molecule has identical neurotrophic power of the native form but a reduced affinity for the p75NTR receptors, known to trigger apoptosis. ...

The accurate estimation of limb state is necessary for movement planning and execution. While state estimation requires both feedforward and feedback information, we focus here on the latter. Prior literature has shown that integrating visual and proprioceptive feedback improves estimates of static limb position. However, differences in visual and proprioceptive feedback delays suggest that multisensory integration could be disadvantageous when the limb is moving. We formalized this hypothesis by modeling feedback-based state estimation using the long-standing maximum likelihood estimation model of multisensory integration, which we updated to account for sensory delays. Our model predicted that the benefit of multisensory integration was largely lost when the limb was passively moving. We tested this hypothesis in a series of experiments in human subjects that compared the degree of interference created by discrepant visual or proprioceptive feedback when estimating limb position either statically at the ...

Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knock-out (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit; instead, impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demo...

Contrast sensitivity (CS), which constrains human vision, decreases from fovea to periphery, from the horizontal to the vertical meridian, and from the lower vertical to the upper vertical meridian. It also depends on spatial frequency (SF), and the contrast sensitivity function (CSF) depicts this relation. To compensate for these visual constraints, we constantly make saccades and foveate on relevant objects in the scene. Already before saccade onset, presaccadic attention shifts to the saccade target and enhances perception. However, it is unknown whether and how it modulates the interplay between CS and SF, and if this effect varies around polar angle meridians. CS enhancement may result from a horizontal or vertical shift of the CSF, increase in bandwidth, or any combination. In addition, presaccadic attention could enhance CS similarly around the visual field, or it could benefit perception more at locations with poorer performance (i.e., vertical meridian). Here, we investigated these possibilities b...

Ca2+-binding proteins (CaBPs; CaBP1–5) are a subfamily of neuronal Ca2+ sensors with high homology to calmodulin. Notably, CaBP4, which is exclusively expressed in rod and cone photoreceptors, is crucial for maintaining normal retinal functions. However, the functional roles of CaBP1, CaBP2, and CaBP5 in the retina remain elusive, primarily due to limited understanding of their expression patterns within inner retinal neurons. In this study, we conducted a comprehensive transcript analysis using single-cell RNA sequencing datasets to investigate the gene expression profiles of CaBPs in mouse and human retinal neurons. Our findings revealed notable similarities in the overall expression patterns of CaBPs across both species. Specifically, nearly all amacrine cell, ganglion cell, and horizontal cell types exclusively expressed CaBP1. In contrast, the majority of bipolar cell types, including rod bipolar (RB) cells, expressed distinct combinations of CaBP1, CaBP2, and CaBP5, rather than a single CaBP as previ...

A multidisciplinary and international convergent working group (neural stem cell biology, functional electrical stimulation, materials engineering, electrical engineering, neurosurgery, neurology, biomedical device, and commercialization) met in Canada to create a call to action for Electrical Stimulation for Neural Repair. Electrical stimulation, in the form of deep brain stimulation (DBS), is an approved treatment for various neurological disorders such as essential tremor, Parkinson's disease, and epilepsy. Here, DBS works through disrupting neural circuits; however, electrical stimulation may also effectively promote neural repair due to the activation of electrosensitive resident neural stem cells. Activating neural stem cells has great promise for enhancing neuroplasticity to treat damaged brains. To realize this therapy's potential, multidisciplinary experts met to identify barriers, gaps, and next steps. Neurological disorders are a leading cause of death and disabilities worldwide and represent a...