A fundamental challenge for bioelectronics is to deliver power to miniature devices inside the body. Wires are common failure points and limit device placement. Wireless power by electromagnetic or ultrasound waves must overcome absorption by the body and impedance mismatches between air, bone, and tissue. Magnetic fields, on the other hand, suffer little absorption by the body or differences in impedance at interfaces between air, bone, and tissue. These advantages have led to magnetically-powered stimulators based on induction or magnetothermal effects. However, fundamental limitations in these power transfer technologies have prevented miniature magneticallypowered stimulators from applications in many therapies and disease models because they do not operate in clinical "high-frequency" ranges above 20 Hz. Here we show that magnetoelectric materials -applied for the first time in bioelectronics devices -enable miniature magnetically-powered neural stimulators that operate at clinically relevant high-frequencies. As an example, we show that ME neural stimulators can effectively treat the symptoms of a Parkinson's disease model in a freely behaving rodent. We also show that ME-powered devices can be miniaturized to sizes smaller than a grain of rice while maintaining effective stimulation voltages. These results suggest that ME materials are an excellent candidate for wireless power delivery that will enable miniature neural stimulators in both clinical and research applications. Wireless neural stimulators have the potential to provide less invasive, longer lasting interfaces to brain regions and peripheral nerves compared to batterypowered devices or wired stimulators. Indeed, wires are a common failure point for bioelectronic devices. Percutaneous wires present a pathway for infection 1 and implanted wires can also limit the ability of the stimulators to move with the tissue, leading to a foreign body response or loss of contact with the target tissue 2,3 . Additionally, chronic stress and strain on wires, particularly for devices in the periphery, can lead to failure in the wire itself or its connection to the stimulator 4 . In small animals like rats and mice, wires used to power neural stimulators can interfere with natural behavior, particularly when studying social interaction between multiple animals 5 .

Epigenetic mechanisms such as DNA methylation are essential regulators of the function and information storage capacity of neurons. DNA methylation is highly dynamic in the developing and adult brain, and is actively regulated by neuronal activity and behavioural experiences. However, it is presently unclear how methylation status at individual genes is targeted for modification. Here, we report that extra-coding RNAs (ecRNAs) interact with DNA methyltransferases and regulate neuronal DNA methylation. Expression of ecRNA species is associated with gene promoter hypomethylation, is altered by neuronal activity, and is overrepresented at genes involved in neuronal function. Knockdown of the Fos ecRNA locus results in gene hypermethylation and mRNA silencing, and hippocampal expression of Fos ecRNA is required for long-term fear memory formation in rats. These results suggest that ecRNAs are fundamental regulators of DNA methylation patterns in neuronal systems, and reveal a promising avenue for therapeutic targeting in neuropsychiatric disease states.

Survival depends on a balance between seeking rewards and avoiding potential threats, but the neural circuits that regulate this motivational conflict remain largely unknown. Using an approach-food vs. avoid-predator threat conflict test in rats, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Inactivation of aPVTCRF neurons during conflict biases animal’s response toward food, whereas activation of these cells recapitulates the food-seeking suppression observed during conflict. aPVTCRF neurons project densely to the nucleus accumbens (NAc), and activity in this pathway reduces food seeking and increases avoidance. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVTCRF neurons, and demonstrated that VMH-aPVT neurons mediate defensive behaviors exclusively during conflict. Together, our findings describe a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats.

The effect of intermittent noise upon attention span was investigated in two experiments. In Exp. 1, 4 levels of noise intensity were used (no noise, 75 db, 85 db, and 100 db). The task was a serial anticipation task in which the relevant stimuli were 4-letter words located in the center of a projected slide. 3-letter words were peripherally located; the peripheral words were not mentioned to Ss. Ss in the 85-db and the 100-db conditions learned fewer of the peripheral words as indicated by a free-recall test than Ss in the no-noise and the 75-db conditions, indicating a narrowing of attention due to the higher noise levels. In Exp. 2, Ss operating under noise (85 db) performed significantly better on the Stroop Color-Word Test than did Ss operating under no noise, again indicating a focusing of attention due to noise-induced arousal. The results are consistent with the proposal of several authors that increasing emotional arousal causes a narrowing of attention.

A fundamental challenge for bioelectronics is to deliver power to miniature devices inside the body. Wires are common failure points and limit device placement. On the other hand, wireless power by electromagnetic or ultrasound waves must overcome absorption by the body and impedance mismatches between air, bone, and tissue. In contrast, magnetic fields suffer little absorption by the body or differences in impedance at interfaces between air, bone, and tissue. These advantages have led to magneticallypowered stimulators based on induction or magnetothermal effects. However, fundamental limitations in these power transfer technologies have prevented miniature magnetically-powered stimulators from applications in many therapies and disease models because they do not operate in clinical "highfrequency" ranges above 50 Hz. Here we show that magnetoelectric materials -applied in bioelectronic devices -enable miniature magnetically-powered neural stimulators that can operate up to clinically-relevant high-frequencies.As an example, we show that ME neural stimulators can effectively treat the symptoms of a hemi-Parkinson's disease model in freely behaving rodents. We further demonstrate that ME-powered devices can be miniaturized to mmsized devices, fully implanted, and wirelessly powered in freely behaving rodents. These results suggest that ME materials are an excellent candidate for wireless power delivery that will enable miniature bioelectronics for both clinical and research applications.

Epidemiology studies have found that a comorbidity exists between traumatic brain injury (TBI) and stress-related disorders. However, the anatomical and cellular bases for this association is poorly understood. An inability to extinguish the memory of a traumatic event lies at the core of many stress-related disorders. Experimental studies have shown that the medial pre-frontal cortex (mPFC), especially the infralimbic (IL) cortex, is required for extinction and for storing the memory of extinction. The output from the central nucleus of amygdala projects to the lateral hypothalamus, paraventricular nucleus, and central gray to regulate heart rate, stress hormone release, and freezing behavior, respectively. Projection neurons of the IL (layers II/III pyramidal neurons) are thought to stimulate GABAergic neurons in the amygdala, which, in turn, inhibit central amygdala output and reduce fear expression. Thus, loss and/or altered morphology of projection neurons of IL as a result of a mild TBI (mTBI) can compromise their ability to effectively inhibit the central amygdala, allowing the original fear memory to drive behavior. Using lateral mild fluid percussion injury (mFPI) in rats, we found that mFPI did not reduce neuronal numbers in the IL, but caused a significant reduction in overall dendritic spine density of both basal and apical dendrites on layer II/III pyramidal neurons. Spine numbers on layer V/VI pyramidal neurons were not significantly changed as a result of mFPI. The reduction in spine density on layer II/III pyramidal neurons we observed may diminish the efficacy of these neurons to inhibit the output of the central amygdala, thereby reducing the ability of the IL to suppress fear responses after extinction training. Consistent with this, mFPI rats display enhanced freezing behavior during and after extinction training as compared to sham-operated controls, although the ability to form contextual fear memories was not impaired. These results may have implications in stress-related disorders associated with mTBI.

During sleep, neurons in the thalamic reticular nucleus (TRN) participate in distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory relay nuclei are known to underlie the generation of sleep spindles, the mechanisms regulating slow (,1 Hz) forms of thalamic oscillations are not well understood. Under in vitro conditions, TRN neurons can generate slow oscillations in a cell-intrinsic manner, with postsynaptic Group 1 metabotropic glutamate receptor activation triggering long-lasting plateau potentials thought to be mediated by both T-type Ca 21 currents and Ca 21 -activated nonselective cation currents (I CAN ). However, the identity of I CAN and the possible contribution of thalamic circuits to slow rhythmic activity remain unclear. Using thalamic slices derived from adult mice of either sex, we recorded slow forms of rhythmic activity in TRN neurons, which were driven by fast glutamatergic thalamoreticular inputs but did not require postsynaptic Group 1 metabotropic glutamate receptor activation. For a significant fraction of TRN neurons, synaptic inputs or brief depolarizing current steps led to long-lasting plateau potentials and persistent firing (PF), and in turn, resulted in sustained synaptic inhibition in postsynaptic relay neurons of the ventrobasal thalamus (VB). Pharmacological approaches indicated that plateau potentials were triggered by Ca 21 influx through T-type Ca 21 channels and mediated by Ca 21 -and voltage-dependent transient receptor potential melastatin 4 (TRPM4) channels. Together, our results suggest that thalamic circuits can generate slow oscillatory activity, mediated by an interplay of TRN-VB synaptic circuits that generate rhythmicity and TRN cell-intrinsic mechanisms that control PF and oscillation frequency.

The effect of emotional arousal, as induced by broad-band noise, upon breadth of attention was investigated. Four intensity levels were employed (no noise, 75 db, 85 db, and 100 db). Two of the tasks, Stroop color-word test, rod-and-frame test, required narrowed attention and the third, Tsai-Partington pathways test, required broader attention. Arousal level did not significantly affect performance on the rod-and-frame test or the pathways test, althouth in the latter a curvilinear trend was suggested. A complex relationship between arousal level and Stroop performance was obtained; performance of the 85-db group was superior to that of other groups, which did not differ significantly from one another. Results were discussed in terms of Easterbrook's (1959) arousal hypothesis.