In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB)-score. In comparison, CatWalk is an automated gait analysis system, providing further parameter specifications. Although together the CatWalk parameters encompass gait, studies consistently report single parameters, which differ in significance from other behavioral assessments. Therefore, we believe no single parameter produced by the CatWalk can represent the fully-coordinated motion of gait. Typically, other locomotor assessments, such as the BBB-score, combine several locomotor characteristics into a representative score. For this reason, we ranked the most distinctive CatWalk parameters between uninjured and SC injured rats. Subsequently, we combined nine of the t...

Tactile sensation is one of our primary means to collect information about the nearby environment and thus crucial for daily activities and survival. Therefore, it is of high importance to restore sensory feedback after sensory loss. Optogenetic manipulation allows local or pathway specific write-in of information. However, it remains elusive whether optogenetic stimulation can be interpreted as tactile sensation to guide operant behavior and how it is integrated with tactile stimuli. To address these questions we employed a vibrotactile detection task combined with optogenetic neuromodulation in freely moving rats. By bidirectionally manipulating the activity of neurons in primary somatosensory cortex (S1), we demonstrated that optical activation as well as inhibition of S1 reduced the detection rate for vibrotactile stimuli. Interestingly, activation of corticostriatal terminals improved the detection of tactile stimuli, while inhibition of corticostriatal terminals did not affect the performance. To man...

Mutations in the presenilin genes ( PS1 , PS2 ) have been linked to the majority of familial Alzheimer’s disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated PS1 conditional knockout induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional PS2 knockout. We showed that iPSC-derived neural progenitor cells do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated PS -null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human PS1 / PS2 -null neurons along with a concomitant accumulatio...

According to the organizational-activational hypothesis, organizational effects of testosterone during (prenatal) brain development moderate activational effects of adult testosterone on behavior. Accumulating evidence supports the notion that adolescence is another period during which sex hormones organize the nervous system. Here we investigate how pubertal sex- hormones moderate the activational effects of adult sex-hormones on social cognition in humans. To do so, we recruited a sample of young men (n=507, ∼ 19 years of age) from a longitudinal birth cohort, and investigated if testosterone exposure during adolescence (from 9 to 17 years of age) moderates the relation between current testosterone and brain response to faces in young adulthood, as assessed with functional magnetic resonance imaging (fMRI). Our results showed that the cumulative exposure to testosterone during adolescence moderated the relation between adult testosterone and both the mean fMRI response and functional connectivity (i.e., ...

Motor adaptation is commonly thought to be a trial-and-error process in which the accuracy of movement improves with repetition of behavior. We challenged this view by testing whether erroneous movements are necessary for motor adaptation. In the eye movement system, the association between movements and errors can be disentangled, since errors in the predicted stimulus trajectory can be perceived even without movements. We modified a smooth pursuit eye movement adaptation paradigm in which monkeys learn to make an eye movement that predicts an upcoming change in target direction. We trained the monkeys to fixate on a target while covertly, an additional target initially moved in one direction and then changed direction after 250 ms. The monkeys showed a learned response to infrequent probe trials in which they were instructed to follow the moving target. Further experiments confirmed that probing learning or residual eye movements during fixation did not drive learning. These results show that motor adapt...

Patch-clamp instruments including amplifier circuits and pipettes affect the recorded voltage signals. We hypothesized that realistic and complete in silico representation of recording instruments together with detailed morphology and biophysics of small recorded structures will reveal signal distortions and provide a tool that predicts native, instrument-free electrical signals from distorted voltage recordings. Therefore, we built a model that was verified by small axonal recordings. The model accurately recreated actual action potential measurements with typical recording artefacts and predicted the native electrical behavior. The simulations verified that recording instruments substantially filter voltage recordings. Moreover, we revealed that instrumentation directly interferes with local signal generation depending on the size of the recorded structures, which complicates the interpretation of recordings from smaller structures, such as axons. However, our model offers a straightforward approach that...

For some individuals, social stress is a risk factor for psychiatric disorders characterised by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorised them as “resilient” or “susceptible” based on social avoidance behaviour. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic dopamine regions and would have enduring consequences on PFC dopamine connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behaviour, AcSD in adulthood leads to a majority ...

The effective connectivity of brain networks can be assessed using functional magnetic resonance imaging (fMRI) to quantify the effects of local electrical microstimulation (EM) on distributed neuronal activity. The delivery of EM to specific brain regions, particularly with layer specificity, requires MRI compatible equipment that provides fine control of a stimulating electrode’s position within the brain while minimizing imaging artifacts. To this end, we developed a microdrive made entirely of MRI compatible materials. The microdrive uses an integrated penetration grid to guide electrodes and relies on a micro-drilling technique to eliminate the need for large craniotomies, further reducing implant maintenance and image distortions. The penetration grid additionally serves as a built-in MRI marker, providing a visible fiducial reference for estimating probe trajectories. Following the initial implant procedure, these features allow for multiple electrodes to be inserted, removed, and repositioned with ...

The Lateral Orbito-Frontal Cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship. Damage to the LOFC impairs behavioral flexibility in humans and is associated with sub-optimal performance in reward devaluation protocols in rodents. As chronic intermittent ethanol (CIE) exposure also impairs OFC-dependent behaviors, we hypothesized that CIE exposure would alter LOFC neuronal activity during alcohol drinking, especially under conditions when the reward value of ethanol was modulated by aversive or appetitive tastants. To test this hypothesis, we monitored LOFC activity using GCaMP6f fiber photometry in mice receiving acute injections of ethanol and in those trained in operant ethanol self-administration. In naïve mice, an acute injection of ethanol caused a dose-dependent decrease in ...

Cochlear outer hair cells (OHCs) are known to uniquely participate in auditory processing through their electromotility, and like inner hair cells (IHCs), are also capable of releasing vesicular glutamate onto spiral ganglion (SG) neurons; in this case onto the sparse type II SG neurons. However, unlike glutamate signaling at the inner hair cell (IHC) -type I SG synapse, which is robust across a wide spectrum of sound intensities, glutamate signaling at the OHC-type II SG synapse is weaker and has been hypothesized to occur only at intense, possibly damaging sound levels. Here, we tested the ability of the OHC-type II SG pathway to signal to the brain in response to moderate, non-damaging sound (80 dB SPL) as well as to intense sound (115 dB SPL). First, we determined the vesicular glutamate transporters (VGLUTs) associated with OHC signaling and then confirmed the loss of glutamatergic synaptic transmission from OHCs to type II SG neurons in knockout mice using dendritic patch-clamp recordings. Next, we g...