Older adults tend to display greater brain activation in the non-dominant hemisphere during even basic sensorimotor responses. It is debated whether this Hemispheric Asymmetry Reduction in Older Adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving adult-lifespan human samples (N = 586 and N = 81; approximately half female) who performed right hand finger responses, we distinguished between these hypotheses using behavioural and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in- and out-of-scanner behavioural results both demonstrated evidence against a compensatory relationship, in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduc...

At rest, mammalian brains display remarkable spatiotemporal complexity, evolving through recurrent functional connectivity states on a slow timescale of the order of tens of seconds. While the phenomenology of the resting state dynamics is valuable in distinguishing healthy and pathological brains, little is known about its underlying mechanisms. Here, we identify neuronal cascades as a potential mechanism. Using full-brain network modeling, we show that neuronal populations, coupled via a detailed structural connectome, give rise to large-scale cascades of firing rate fluctuations evolving at the same time scale of resting-state networks. The ignition and subsequent propagation of cascades depend upon the brain state and connectivity of each region. The largest cascades produce bursts of Blood-Oxygen-Level-Dependent (BOLD) co-fluctuations at pairs of regions across the brain, which shape the simulated resting-state network dynamics.We experimentally confirm these theoretical predictions. We demonstrate th...

Normal aging is associated with a decline in memory and motor learning ability. However, the exact form of these impairments (e.g., the short-term temporal stability and affected learning mechanisms) is largely unknown. Here, we utilized a sensorimotor adaptation task to examine changes in the temporal stability of two forms of learning (explicit and implicit) due to normal aging. Healthy young (ages 19-28, 20 individuals) and older human subjects (ages 63-85, 19 individuals) made reaching movements in response to altered visual feedback. On each trial subjects turned a rotation dial to select an explicit aiming direction. Once selected, the display was removed and subjects moved the cursor from the start position to the target. After initial training with the rotational feedback perturbation, subjects completed a series of probe trials at different delay periods to systematically assess the short-term retention of learning. For both groups the explicit aiming showed no significant decrease over 1.5 minute...

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISI) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e. morning and afternoon sessions on two days, five to seven days apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intra- nor inter-observer measures of SICI differed significantly between examinations, except for T-SICI at ISI 3ms (P=0.00035) and A-SICI at ISI 2.5ms (P=0.0103). Intra-day reliability was poor-to-good for A-SICI and m...

Sex steroid hormones act on hypothalamic kisspeptin neurons to regulate reproductive neural circuits in the brain. Kisspeptin neurons start to express estrogen receptors (ERs) in utero , suggesting steroid hormone action on these cells early during development. Whether neurosteroids are locally produced in the embryonic brain and impinge onto kisspeptin/reproductive neural circuitry is not known. To address this question, we analyzed aromatase expression, a key enzyme in estrogen synthesis, in male and female mouse embryos. We identified an aromatase neuronal network comprising ∼6000 neurons in the hypothalamus and amygdala. By birth, this network has become sexually dimorphic in a cluster of aromatase neurons in the arcuate nucleus adjacent to kisspeptin neurons. We demonstrate that male arcuate aromatase neurons convert testosterone to estrogen to regulate kisspeptin neuron activity. We provide spatio-temporal information on aromatase neuronal network development and highlight a novel mechanism whereby a...

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, their activity profiles across the course of fear learning, and whether or how these change across the course of learning each remain poorly understood. Here we used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats during Pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events but their activity during moments of non-reinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to unexpected than ex...

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the non-selective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic acetylcholine receptor activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the thresh...

The non-human primate (NHP) constitutes an extraordinarily important model in neuroscience research for understanding the neuronal underpinnings of perceptual, motor, cognitive, and executive functions of the primate brain, and to study the physiological causes, effects, and potential treatments of brain disorders. Due to their cognitive capabilities, NHPs receive special attention in Animal Welfare Regulations around the world, and their well-being is a benchmark for the evaluation, monitoring, and refinement of experimental procedures. As a consequence, many typical neuroscientific procedures are considered only mildly severe by animal welfare boards. There is, however, an ongoing debate about possible long-term and cumulative effects. Due to a lack of longitudinal data, it is unclear whether mildly severe procedures may cause more significant harm on the long-term, and to what extent they may impact animal well-being and healthiness over time. We here make use of a database of blood samples drawn over a...

Dopaminergic modulation is essential for the control of voluntary movement, however the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined if chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson’s disease, was sufficient to shift M1 neuron excitability. We show that D1 and D2 receptor (D1R, D2R) antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In co...

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to ‘injure’ the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or non-affected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development...