Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRsNav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRsNav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. Howev...

How the human brain reconstructs, step-by-step, the core elements of past experiences is still unclear. Here, we map the spatiotemporal trajectories along which visual object memories are reconstructed during associative recall. Specifically, we inquire whether retrieval reinstates feature representations in a copy-like but reversed direction with respect to the initial perceptual experience, or alternatively, this reconstruction involves format transformations and regions beyond initial perception. Participants from two cohorts studied new associations between verbs and randomly paired object images, and subsequently recalled the objects when presented with the corresponding verb cue. We first analyze multivariate fMRI patterns to map where in the brain high- and low-level object features can be decoded during perception and retrieval, showing that retrieval is dominated by conceptual features, represented in comparatively late visual and parietal areas. A separately acquired EEG dataset is then used to t...

Conscious reportability of visual input is associated with a bimodal neural response in the primary visual cortex (V1): an early-latency response coupled to stimulus features and a late-latency response coupled to stimulus report or detection. This late wave of activity, central to major theories of consciousness, is thought to be driven by the prefrontal cortex (PFC), responsible for “igniting” it. Here we analyzed two electrophysiological studies in mice performing different stimulus detection tasks and characterized neural activity profiles in three key cortical regions: V1, posterior parietal cortex (PPC), and PFC. We then developed a minimal network model, constrained by known connectivity between these regions, reproducing the spatiotemporal propagation of visual- and report-related activity. Remarkably, while PFC was indeed necessary to generate report-related activity in V1, this occurred only through the mediation of PPC. PPC, and not PFC, had the final veto in enabling the report-related late wav...

Social recognition is an essential part of social function and often promotes specific social behaviors based on prior experience. Social and defensive behaviors in particular often emerge with prior experiences of familiarity or novelty/stress, respectively. This is also commonly seen in rodents toward same-strain and interstrain conspecifics. Medial amygdala (MeA) activity guides social choice based on age and sex recognition and is sensitive to social experiences. However, little is known about whether the MeA exhibits differential responses based on strain or how this is impacted by experience. Social stress impacts posterior MeA (MeAp) function and can shift measures of social engagement. However, it is unclear how stress impacts MeAp activity and contributes to altered social behavior. The primary goal of this study in adult male Sprague Dawley rats was to determine whether prior stress experience with a different-strain (Long–Evans) rat impacts MeAp responses to same-strain and different-strain cons...

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 ...