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 ...

Pavlovian conditioning tasks have been used to identify the neural systems involved with learning cue–outcome relationships. In delay conditioning, the conditioned stimulus (CS) overlaps or co-terminates with the unconditioned stimulus (US). Prior studies demonstrate that dopamine in the nucleus accumbens (NAc) regulates behavioral responding during delay conditioning. Furthermore, the dopamine response to the CS reflects the relative value of the upcoming reward in these tasks. In contrast to delay conditioning, trace conditioning involves a “trace” period separating the end of the CS and the US delivery. While dopamine has been implicated in trace conditioning, no studies have examined how NAc dopamine responds to reward-related stimuli in these tasks. Here, we developed a within-subject trace conditioning task where distinct CSs signaled either a short trace period (5 s) or a long trace period (55 s) prior to food reward delivery. Male rats exhibited greater conditioned responding and a faster response ...

Histone deacetylase 3 (HDAC3) is one of the most highly expressed HDACs in the brain shown to be a negative regulator of long-term memory formation. HDAC3 has also been shown to be involved in cocaine-associated behaviors, demonstrated by manipulations in the nucleus accumbens. Previous studies have demonstrated that expression of a dominant negative of a key HDAC3 target gene, nuclear receptor subfamily 4 group A member 2 (NR4A2), in cholinergic neurons of the medial habenula (MHb) blocked reinstatement of cocaine-induced conditioned place preference (CPP) as well as cue-induced intravenous self-administration (IVSA). Together, these findings suggested that HDAC3 would also be important for MHb-dependent reinstatement of CPP and IVSA, which we examined in this study. Contrary to our hypothesis, our results found that expression of an HDAC3 deacetylase dead point mutant within the cholinergic neurons of the mouse MHb had no effect on reinstatement or other cocaine-induced behaviors.

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...

Research that combines advanced technological devices with complex behavioral tasks has enabled investigations into the neural mechanisms underlying brain and behavioral states. Freely moving rodent experiments often require a tether—a wired connection between an implanted device and an external power supply or data acquisition system. Traditionally, these experiments have used passive commutators to manage tethers, but such setups are often inadequate for reducing twisting and mechanical strain during behavioral tasks. Existing motorized commutators have extended the range of motion for these experiments but generally rely on stepper motors that produce auditory noise, potentially interfering with behavior. To address these limitations, we developed the Motor Assisted Commutator to Harness Electronics in Tethered Experiments (MACHETE), a motor-assisted commutator featuring a low-noise brushless motor. MACHETE dynamically adjusts tethers based on mouse movement, reducing torque and mechanical strain, and m...

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...

Principal neurons (PNs) of the lateral superior olive (LSO) are a critical component of brain circuits that compare information between the two ears to extract sound source-location-related cues. LSO PNs are not a homogenous group but differ in their transmitter type, intrinsic membrane properties, and projection pattern to higher processing centers in the inferior colliculus. Glycinergic inhibitory LSO PNs have higher input resistance than glutamatergic excitatory LSO PNs (∼double). This suggests that the inhibitory cell type has a lower minimum input or signal intensity required to produce an output (activation threshold) which may impact how they integrate binaural inputs. However, cell-type-specific differences in the strength of synaptic drive could offset or accentuate such differences in intrinsic excitability and have not been assessed. To evaluate this possibility, we used a knock-in mouse model to examine spontaneous and electrically stimulated (evoked) synaptic events in LSO PN types using volta...