Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer’s disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased...

Peripheral nerve injuries (PNIs) induce the retraction from the ventral horn of the synaptic collaterals of Ia afferents injured in the nerve, effectively removing Ia synapses from α-motoneurons. The loss of Ia input impairs functional recovery and could explain, in part, better recovery after PNIs with better Ia synaptic preservation. Synaptic losses correlate with injury severity, speed, and efficiency of muscle reinnervation and requires ventral microglia activation. It is unknown whether this plasticity is age dependent. In neonates, axotomized motoneurons and sensory neurons undergo apoptosis, but after postnatal day 10 most survive. The goal of this study was to analyze vesicular glutamate transporter 1 (VGluT1)-labeled Ia synapses (which also include II afferents) after nerve crush in 10 day old rats, a PNI causing little Ia/II synapse loss in adult rats. We confirmed fast and efficient reinnervation of leg muscles; however, a massive number of VGluT1/Ia/II synapses were permanently lost. This synap...

Functional magnetic resonance spectroscopy (fMRS) of GABA at 3 T poses additional challenges compared with fMRS of other metabolites because of the difficulties of measuring GABA levels; GABA is present in the brain at relatively low concentrations, and its signal is overlapped by higher concentration metabolites. Using 7 T fMRS, GABA levels have been shown to decrease specifically during motor learning (and not during a control task). Though the use of 7 T is appealing, access is limited. For GABA fMRS to be widely accessible, it is essential to develop this method at 3 T. Nine healthy right-handed participants completed a motor learning and a control button-pressing task. fMRS data were acquired from the left sensorimotor cortex during the task using a continuous GABA-edited MEGA-PRESS acquisition at 3 T. We found no significant changes in GABA+/tCr, Glx/tCr, or Glu/tCr levels in either task; however, we show a positive relationship between motor learning and glutamate levels both at rest and at the star...

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled tri...

Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds (“flicker”). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here, we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional...

In the article, “The Planning Horizon for Movement Sequences,” by Giacomo Ariani, Neda Kordjazi, J. Andrew Pruszynski, and Jörn Diedrichsen, which published online on March 22, 2021, …

We must often decide how much effort to exert or withhold to avoid undesirable outcomes or obtain rewards. In depression and anxiety, levels of avoidance can be excessive and reward-seeking may be reduced. Yet outstanding questions remain about the links between motivated action/inhibition and anxiety and depression levels, and whether they differ between men and women. Here, we examined the relationship between anxiety and depression scores, and performance on effortful active and inhibitory avoidance (Study 1) and reward seeking (Study 2) in humans. Undergraduates and paid online workers (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mi>N</mml:mi><mml:mrow><mml:mi>A</mml:mi><mml:mi>v</mml:mi><mml:mi>o</mml:mi><mml:mi>i</mml:mi><mml:mi>d</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> = 545, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mi>N</mml:mi><mml:mrow><mml:mi>R</mml:mi><mml:mi>e</mml:mi>...

Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo , and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice; GdnfcHyper ). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor sympt...

Circadian photoperiod, or day length, changes with the seasons and influences behavior to allow animals to adapt to their environment. Photoperiod is also associated with seasonal rhythms of affective state, as evidenced by seasonality of several neuropsychiatric disorders. Interestingly, seasonality tends to be more prevalent in women for affective disorders such as major depressive disorder and bipolar disorder (BD). However, the underlying neurobiological processes contributing to sex-linked seasonality of affective behaviors are largely unknown. Mesolimbic dopamine input to the nucleus accumbens (NAc) contributes to the regulation of affective state and behaviors. Additionally, sex differences in the mesolimbic dopamine pathway are well established. Therefore, we hypothesize that photoperiod may drive differential modulation of NAc dopamine in males and females. Here, we used fast-scan cyclic voltammetry (FSCV) to explore whether photoperiod can modulate subsecond dopamine signaling dynamics in the NAc...

The motor cortex controls skilled arm movement by recruiting a variety of targets in the nervous system, and it is important to understand the emergent activity in these regions as refinement of a motor skill occurs. One fundamental projection of the motor cortex (M1) is to the cerebellum. However, the emergent activity in the motor cortex and the cerebellum that appears as a dexterous motor skill is consolidated is incompletely understood. Here, we report on low-frequency oscillatory (LFO) activity that emerges in cortico-cerebellar networks with learning the reach-to-grasp motor skill. We chronically recorded the motor and the cerebellar cortices in rats, which revealed the emergence of coordinated movement-related activity in the local-field potentials as the reaching skill consolidated. Interestingly, we found this emergent activity only in the rats that gained expertise in the task. We found that the local and cross-area spiking activity was coordinated with LFOs in proficient rats. Finally, we also f...