Neural systems use homeostatic plasticity to maintain normal brain functions and to prevent abnormal activity. Surprisingly, homeostatic mechanisms that regulate circuit output have mainly been demonstrated during artificial and/or pathological perturbations. Natural, physiological scenarios that activate these stabilizing mechanisms in neural networks of mature animals remain elusive. To establish the extent to which a naturally inactive circuit engages mechanisms of homeostatic plasticity, we utilized the respiratory motor circuit in bullfrogs that normally remains inactive for several months during the winter. We found that inactive respiratory motoneurons exhibit a classic form of homeostatic plasticity, up-scaling of AMPA-glutamate receptors. Up-scaling increased the synaptic strength of respiratory motoneurons and acted to boost motor amplitude from the respiratory network following months of inactivity. Our results show that synaptic scaling sustains strength of the respiratory motor output following months of inactivity, thereby supporting a major neuroscience hypothesis in a normal context for an adult animal.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5–9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

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Noradrenergic tuning, not simple rate effects, produces temperature-sensitivity of the respiratory network in bullfrogs Animals match ventilation to metabolic and acid-base regulatory demands during changes in body temperature. Across vertebrates ventilation increases at warmer temperatures and decreases at cooler temperatures. At the organismal level this is attributed to metabolic feedback and/or alpha-stat pH regulation; however, the cellular mechanisms that produce ventilatory output in response to brain temperature changes remain unclear. To identify mechanisms underlying temperature-sensitivity of the respiratory control network, I used brainstem-spinal cord preparations producing spontaneously active, rhythmic motor output similar to breathing in vivo of adult bullfrogs Lithobates catesbeianus. In vitro brainstem-spinal cords were superfused with artificial cerebrospinal fluid (aCSF) equilibrated at 90% O 2 , 1.3% CO 2 , and balance N 2 .Whole nerve recordings from the trigeminal (V) and vagus (X) nerves were used for measuring respiratory-related activity. I applied temperature ramps from 20ºC to 15ºC and then to 25ºC; each step lasted 15 minutes. Bursting frequency was analyzed for the last 5 minutes of each step and then normalized to percent of baseline (20ºC). Consistent with in vivo and in vitro data (Bícego-Nahas and Branco, 1999;Morales and Hedrick, 2002), I demonstrate that the frequency of respiratory-related nerve activity is stable iv across high temperatures, but not lower temperatures (One-way ANOVA p<0.0002; burst frequency different at 15ºC compared to 20ºC and compared to 25ºC, but no difference between 20ºC and 25ºC; Tukey's Multiple Comparison post hoc test). The locus coeruleus (LC) is a nucleus of the respiratory network and is the main supplier of norepinephrine in the brain. LC neurons from bullfrogs are paradoxically activated by decreases in temperature suggesting that firing frequencies inversely proportional to temperature may play a role in setting the respiratory frequency across temperatures. To identify the role of norepinephrine in generating the respiratory frequency, I applied the temperature protocol while blocking the main adrenergic receptors (AR). For blocking α 1 AR, preparations were superfused with aCSF containing prazosin and for blocking α 2 AR I used RX821002. I found that bursting stability at high temperatures is disrupted when α 1 AR are blocked (One-way ANOVA p<0.0001; burst frequency significantly lower at 15ºC compared to 20ºC and 25ºC, and significantly lower at 20ºC compared to 25ºC; Tukey's Multiple Comparison post hoc test). In contrast, stable pattern across warm temperatures was maintained while the inhibition of bursting at 15°C was lost when α 2 AR were blocked (One-way ANOVA p=0.025; Tukey's Multiple Comparison post hoc test showed no difference in burst frequency between 15ºC, 20ºC and 25ºC). These results imply that norepinephrine tuning through different receptors, rather than simple Q 10 effects, plays a major role in generating the breathing ...

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