Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer’s disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2–3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11–20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcrip...

Currently there are numerous methods to evaluate peripheral nerve stimulation interfaces in rats, with stimulation-evoked ankle torque being one of the most prominent. Commercial rat ankle torque measurement systems and custom one-off solutions have been published in the literature. However, commercial systems are proprietary and costly and do not allow for customization. One-off lab-built systems have required specialized machining expertise, and building plans have previously not been made easily accessible. Here, detailed building plans are provided for a low-cost, open-source, and basic ankle torque measurement system from which additional customization can be made. A hindlimb stabilization apparatus was developed to secure and stabilize a rat's hindlimb, while allowing for simultaneous ankle-isometric torque and lower limb muscle electromyography (EMG). The design was composed mainly of adjustable 3D-printed components to accommodate anatomical differences between rat hindlimbs. Additionally, construc...

Auditory perception can be significantly disrupted by noise. To discriminate sounds from noise, auditory scene analysis (ASA) extracts the functionally relevant sounds from acoustic input. The zebra finch communicates in noisy environments. Neurons in their secondary auditory pallial cortex (caudomedial nidopallium, NCM) can encode song from background chorus, or scenes, and this capacity may aid behavioral ASA. Furthermore, song processing is modulated by the rapid synthesis of neuroestrogens when hearing conspecific song. To examine whether neuroestrogens support neural and behavioral ASA in both sexes, we retrodialyzed fadrozole (aromatase inhibitor, FAD) and recorded in vivo awake extracellular NCM responses to songs and scenes. We found that FAD affected neural encoding of songs by decreasing responsiveness and timing reliability in inhibitory (narrow-spiking), but not in excitatory (broad-spiking) neurons. Congruently, FAD decreased neural encoding of songs in scenes for both cell types, particularly...

Neural dedifferentiation, the finding that neural representations tend to be less distinct in older adults compared with younger adults, has been associated with age-related declines in memory performance. Most studies assessing the relation between memory and neural dedifferentiation have evaluated how age impacts the distinctiveness of neural representations for different visual categories (e.g., scenes and objects). However, how age impacts the quality of neural representations at the level of individual items is still an open question. Here, we present data from an age-comparative fMRI study that aimed to understand how the distinctiveness of neural representations for individual stimuli differs between younger and older adults and relates to memory outcomes. Pattern similarity searchlight analyses yielded indicators of neural dedifferentiation at the level of individual items as well as at the category level in posterior occipital cortices. We asked whether age differences in neural distinctiveness at...

Layer 4 of the rodent somatosensory cortex has unitary structures called barrels that receive tactile information from individual vibrissae. Barrels in the anterolateral barrel subfield (ALBSF) are much smaller and have gained less attention than larger barrels in the posteromedial barrel subfield (PMBSF), though the former outnumber the latter. We compared the morphological features of barrels between the ALBSF and PMBSF in male mice using deformation-free tangential sections and confocal optical slice-based, precise reconstructions of barrels. The average volume of a single barrel in the ALBSF was 34.7% of that in the PMBSF, but the numerical density of parvalbumin (PV)-positive interneurons in the former was 1.49 times higher than that in the latter. Moreover, PV neuron density in septa was 2.08 times higher in the ALBSF than that in the PMBSF. The proportions of PV neuron number to both all neuron number and all GABAergic neuron number in the ALBSF were also higher than those in the PMBSF. Somata of PV...

Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and motion direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute patients (<3 months post-V1 stroke) and 12 chronic patients (>6 months post-V1 stroke) were pretested and then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts as their performance improved. At baseline, more subacute than chronic participants could correctly discrimi...

GPR4 is a proton-sensing G-protein-coupled receptor implicated in many peripheral and central physiological processes. GPR4 expression has previously been assessed only via detection of the cognate transcript or indirectly, by use of fluorescent reporters. In this work, CRISPR/Cas9 knock-in technology was used to encode a hemagglutinin (HA) epitope tag within the endogenous locus of Gpr4 and visualize GPR4-HA in the mouse central nervous system using a specific, well-characterized HA antibody; GPR4 expression was further verified by complementary Gpr4 mRNA detection. HA immunoreactivity was found in a limited set of brain regions, including in the retrotrapezoid nucleus (RTN), serotonergic raphe nuclei, medial habenula, lateral septum, and several thalamic nuclei. GPR4 expression was not restricted to cells of a specific neurochemical identity as it was observed in excitatory, inhibitory, and aminergic neuronal cell groups. HA immunoreactivity was not detected in brain vascular endothelium, despite clear e...

When learning a new motor skill, people often must use trial and error to discover which movement is best. In the reinforcement learning framework, this concept is known as exploration and has been linked to increased movement variability in motor tasks. For locomotor tasks, however, increased variability decreases upright stability. As such, exploration during gait may jeopardize balance and safety, making reinforcement learning less effective. Therefore, we set out to determine if humans could acquire and retain a novel locomotor pattern using reinforcement learning alone. Young healthy male and female participants walked on a treadmill and were provided with binary reward feedback (indicated by a green checkmark on the screen) that was tied to a fixed monetary bonus, to learn a novel stepping pattern. We also recruited a comparison group who walked with the same novel stepping pattern but did so by correcting for target error, induced by providing real-time veridical visual feedback of steps and a targe...

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitori...

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting gamma-aminobutyric acid type A receptors (GABAARs) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that gamma-aminobutyric acid type A receptors containing the α1 subunit (α1GABAARs) are primarily located in the synapse, whereas gamma-aminobutyric acid type A receptors containing the α5 subunit (α5GABAARs) are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected an siRNA into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the synapse wou...