Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method that has been used to treat various brain disorders. The modulatory effects of rTMS can be adjusted by changing the repetition patterns. Theta-burst magnetic stimulation (TBS) is a magnetic stimulation pattern that can induce long-lasting modulatory effects with a short stimulation period. However, its effects on auditory brain regions remain unclear because of a lack of animal studies in which invasive techniques allow for a detailed exploration of the underlying neural mechanisms. In the current study, we investigated the effects of TBS on the C57BL/6J mouse auditory cortex using a custom-built 7 mm magnetic stimulation coil. Extracellular recordings were made before, during, and after the application of intermittent TBS (iTBS), continuous TBS (cTBS), or sham stimulation. Local field potential amplitudes were increased for 5–20 min post-iTBS compared with the sham condition and were decreased at 10 min post-cTBS compared with the...

The explore/exploit trade-off is a fundamental property of choice selection during reward-guided decision making, where the “same” choice can reflect either of these internal cognitive states. An unanswered question is whether the execution of a decision provides an underexplored measure of internal cognitive states. Touchscreens are increasingly used across species for cognitive testing and afford the ability to measure the precise location of choice touch responses. We examined how male and female mice in a restless bandit decision making task interacted with a touchscreen to determine if the explore/exploit trade-off, prior reward, and/or sex differences change the variability in the kinetics of touchscreen choices. During exploit states, successive touch responses are closer together than those made in an explore state, suggesting exploit states reflect periods of increased motor stereotypy. Although exploit decisions might be expected to be rewarded more frequently than explore decisions, we find that...

Seizures affect a large proportion of the global population and occur due to abnormal neuronal activity in the brain. Unfortunately, widespread genetic and phenotypic heterogeneity contributes to insufficient treatment options. It is critical to identify the genetic underpinnings of how seizures occur to better understand seizure disorders and improve therapeutic development. We used the Drosophila melanogaster model to identify that IGF-II mRNA-binding protein (Imp) is linked to the onset of this phenotype. Specific reduction of Imp in neurons causes seizures after mechanical stimulation. Importantly, gross motor behavior is unaffected, showing Imp loss does not affect general neuronal activity. Developmental loss of Imp is sufficient to cause seizures in adults; thus, Imp-modulated neuron development affects mature neuronal function. Since Imp is an RNA-binding protein, we sought to identify the mRNA target that Imp regulates in neurons to ensure proper neuronal activity after mechanical stress. We find ...

Childhood epilepsy is a common and devastating condition, for which many children still do not have adequate treatment. Some children with drug-resistant epilepsy require surgical excision of epileptogenic brain tissue for seizure control, affording the opportunity to study this tissue ex vivo to interrogate human epileptic neurons for potentially hyperexcitable perturbations in intrinsic electrophysiological properties. In this study, we characterized the diversity of layer L2/3 (L2/3) pyramidal neurons (PNs) in ex vivo brain slices from pediatric patients with epilepsy. We found a remarkable diversity in the firing properties of epileptic L2/3 PNs: five distinct subpopulations were identified. Additionally, we investigated whether the etiology of epilepsy influenced the intrinsic neuronal properties of L2/3 PNs when comparing tissue from patients with epilepsy due to malformations of cortical development (MCDs), other forms of epilepsy (OEs), or with deep-seated tumors. When comparing epileptic with cont...

Despite its central role in the proper functioning of the motor system, sensation has been less studied than motor outputs in sensorimotor adaptation paradigms. This is likely due to the difficulty of measuring sensation non-invasively: while motor outputs have easily observable consequences, sensation is inherently an internal variable of the motor system. In this study, we investigated how well participants can sense relevant sensory stimuli that induce locomotor adaptation. We addressed this question with a split-belt treadmill, which moves the legs at different speeds. We used a two-alternative forced-choice paradigm with multiple repetitions of various speed differences considering the probabilistic nature of perceptual responses. We found that the participants correctly identified a speed difference of 49.7 mm/s in 75% of the trials when walking at 1.05 m/s (i.e., 4.7% Weber Fraction). To gain insight into the perceptual process in walking, we applied a drift-diffusion model (DDM) relating the partic...

In the mammalian primary visual cortex (V1), there are complex interactions between responses to stimuli present in the cell’s classical receptive field (CRF) or “center” and in the surrounding region or “surround.” The circuit mechanisms underlying these behaviors are likely to represent more general cortical mechanisms for integrating information. Here, we develop a circuit model that accounts for three important features of surround suppression (suppression of response to a center stimulus by addition of a surround stimulus): (1) The surround stimulus suppresses the inhibitory and excitatory currents that the cell receives; (2) The strongest suppression arises when the surround orientation matches that of the center stimulus, even when the center stimulus orientation differs from the cell’s preferred orientation; and (3) A surround stimulus of a given orientation most strongly suppresses that orientation’s component of the response to a plaid center stimulus (“feature-specific suppression”). We show tha...

The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific translating ribosome affinity purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young adult (7-10 months) and old (21-24 months) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity ...

Distinct frontal regions make dissociable contributions to rule-guided decision-making, including the ability to learn and exploit associations between abstract rules and reward value, maintain those rules in memory, and evaluate choice outcomes. Value-based learning can be quantified using reinforcement learning (RL) models predicting optimal trial-wise choices and estimating learning rates, which can then be related to the intact functioning of specific brain areas by combining a modeling approach with lesion-behavioral data. We applied a three-parameter feedback-dependent RL model to behavioral data obtained from macaques with circumscribed lesions to the principal sulcus (PS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), superior dorsolateral prefrontal cortex (sdlPFC), and frontopolar cortex (FPC) performing a Wisconsin card sorting task (WCST) analog. Our modeling-based approach identified distinct lesion effects on component cognitive mechanisms contributing to WCST performance. OFC ...

Lactate plays an important role in brain energy metabolism. It contributes to normal brain development and to neuroprotection in diabetic hypoglycemia, but its role in neonatal hypoglycemia is unclear. Moreover, lactate can work as a signaling substance via the lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1). Recent studies indicate that HCAR1 is protective in mouse models of neonatal hypoxic ischemia and has a role in metabolic regulation in glial cells during hypoglycemia. Here we have studied potential impacts of HCAR1 on axonal and myelin development in the cerebral cortex and corpus callosum of young (P21) wild-type (WT) mice and HCAR1 KO mice and in cortical organotypic brain slice cultures. The HCAR1 KO mice showed lower axonal area relative to WT in both cortex and corpus callosum. However, the myelin area was unaffected by HCAR1 KO. Using particle and colocalization analysis, we show that HCAR1 KO predominantly reduces axonal size in unmyelinated axons. Using an organotypic brain slice ...

Cell shape is crucial to cell function, particularly in neurons. The cross-sectional diameter, also known as caliber, of axons and dendrites is an important parameter of neuron shape, best appreciated for its influence on the speed of action potential propagation. Many studies of axon caliber focus on cell-wide regulation and assume that caliber is static. Here, we have characterized local variation and dynamics of axon caliber in vivo using the peripheral axons of zebrafish touch-sensing neurons at embryonic stages, prior to sex determination. To obtain absolute measurements of caliber in vivo, we paired sparse membrane labeling with super-resolution microscopy of neurons in live fish. We observed that axon segments had varicose or “pearled” morphologies and thus vary in caliber along their length, consistent with reports from mammalian systems. Sister axon segments originating from the most proximal branch point in the axon arbor had average calibers that were uncorrelated with each other. Axon caliber a...