Faculty Bibliography

Although the ventromedial hypothalamus ventrolateral area (VMHvl) is now well established as a critical locus for the generation of conspecific aggression, its role is complex, with neurons responding during multiple phases of social interactions with both males and females. It has been previously unclear how the brain uses this complex multidimensional signal and coordinates a discrete action: the attack. Here, we find a hypothalamic-midbrain circuit that represents hierarchically organized social signals during aggression. Optogenetic-assisted circuit mapping reveals a preferential projection from VMHvl^vGlut2 to lPAG^vGlut2 cells, and inactivation of downstream lPAG^vGlut2 populations results in aggression-specific deficits. lPAG neurons are selective for attack action and exhibit short-latency, time-locked spiking relative to the activity of jaw muscles during biting. Last, we find that this projection conveys male-biased signals from the VMHvl to downstream lPAG^vGlut2 neurons that are sensitive to features of ongoing activity, suggesting that action selectivity is generated by a combination of pre- and postsynaptic mechanisms.

The anterior thalamus is a key relay of neuronal signals within the limbic system. During sleep, the occurrence of hippocampal sharp wave-ripples (SWRs), believed to mediate consolidation of explicit memories, is modulated by thalamocortical network activity, yet how information is routed around SWRs and how this communication depends on neuronal dynamics remains unclear. Here, by simultaneously recording ensembles of neurons in the anterior thalamus and local field potentials in the CA1 area of the hippocampus, we show that the head-direction (HD) cells of the anterodorsal nucleus are set in stable directions immediately before SWRs. This response contrasts with other thalamic cells that exhibit diverse couplings to the hippocampus related to their intrinsic dynamics but independent of their anatomical location. Thus, our data suggest a specific and homogeneous contribution of the HD signal to hippocampal activity and a diverse and cell-specific coupling of non-HD neurons.

Cell-permeable photoswitchable small molecules, termed optojasps, are introduced to optically control the dynamics of the actin cytoskeleton and cellular functions that depend on it. These light-dependent effectors were designed from the F-actin-stabilizing marine depsipeptide jasplakinolide by functionalizing them with azobenzene photoswitches. As demonstrated, optojasps can be employed to control cell viability, cell motility, and cytoskeletal signaling with the high spatial and temporal resolution that light affords. Optojasps can be expected to find applications in diverse areas of cell biological research. They may also provide a template for photopharmacology targeting the ubiquitous actin cytoskeleton with precision control in the micrometer range.

Children born very preterm, even in the absence of overt brain injury or major impairment, are at increased risk of cognitive difficulties. This risk is associated with developmental disruptions of the thalamocortical system during critical periods while in the neonatal intensive care unit. The thalamus is an important structure that not only relays sensory information but acts as a hub for integration of cortical activity which regulates cortical power across a range of frequencies. In this study, we investigate the association between atypical power at rest in children born very preterm at school age using magnetoencephalography (MEG), neurocognitive function and structural alterations related to the thalamus using MRI. Our results indicate that children born extremely preterm have higher power at slow frequencies (delta and theta) and lower power at faster frequencies (alpha and beta), compared to controls born full-term. A similar pattern of spectral power was found to be associated with poorer neurocognitive outcomes, as well as with normalized T1 intensity and the volume of the thalamus. Overall, this study provides evidence regarding relations between structural alterations related to very preterm birth, atypical oscillatory power at rest and neurocognitive difficulties at school-age children born very preterm.

INTRODUCTION/BACKGROUND:In addition to neurogenic orthostatic hypotension (nOH), patients with synucleinopathies frequently have hypertension when supine. The long-term consequences of both abnormalities are difficult to disentangle. We aimed to determine if supine hypertension is associated with target organ damage and worse survival in patients with nOH. METHODS:Patients with nOH due to multiple system atrophy (MSA), Parkinson disease (PD), or pure autonomic failure (PAF) were classified into those with or without supine hypertension (systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg). Organ damage was assessed by measuring cerebral white matter hyperintensities (WMH), left ventricular hypertrophy (LVH), and renal function. We prospectively followed patients for 30 months (range: 12-66 months) and recorded incident cardiovascular events and all-cause mortality. RESULTS:Fifty-seven patients (35 with probable MSA, 14 with PD and 8 with PAF) completed all evaluations. In addition to nOH (average fall 35 ± 21/17 ± 14 mmHg, systolic/diastolic, mean ± SD), 38 patients (67%) had supine hypertension (systolic BP > 140 mmHg). Compared to those without hypertension, patients with hypertension had higher blood urea nitrogen levels (P = 0.005), lower estimated glomerular filtration rate (P = 0.008), higher prevalence of LVH (P = 0.040), and higher WMH volume (P = 0.019). Longitudinal follow-up of patients for over 2 years (27.1 ± 14.5 months) showed that supine hypertension was independently associated with earlier incidence of cardiovascular events and death (HR = 0.25; P = 0.039). CONCLUSIONS:Supine hypertension in patients with nOH was associated with an increased risk for target organ damage, cardiovascular events, and premature death. Defining management strategies and safe blood pressure ranges in patients with nOH remains an important research question.

A physiological role for long-chain acyl-CoA esters to activate ATP-sensitive K⁺ (K_ATP) channels is well established. Circulating palmitate is transported into cells and converted to palmitoyl-CoA, which is a substrate for palmitoylation. We found that palmitoyl-CoA, but not palmitic acid, activated the channel when applied acutely. We have altered the palmitoylation state by preincubating cells with micromolar concentrations of palmitic acid or by inhibiting protein thioesterases. With acyl-biotin exchange assays we found that Kir6.2, but not sulfonylurea receptor (SUR)1 or SUR2, was palmitoylated. These interventions increased the K_ATP channel mean patch current, increased the open time, and decreased the apparent sensitivity to ATP without affecting surface expression. Similar data were obtained in transfected cells, rat insulin-secreting INS-1 cells, and isolated cardiac myocytes. Kir6.2ΔC36, expressed without SUR, was also positively regulated by palmitoylation. Mutagenesis of Kir6.2 Cys¹⁶⁶ prevented these effects. Clinical variants in KCNJ11 that affect Cys¹⁶⁶ had a similar gain-of-function phenotype, but was more pronounced. Molecular modeling studies suggested that palmitoyl-C166 and selected large hydrophobic mutations make direct hydrophobic contact with Kir6.2-bound PIP₂ Patch-clamp studies confirmed that palmitoylation of Kir6.2 at Cys¹⁶⁶ enhanced the PIP₂ sensitivity of the channel. Physiological relevance is suggested since palmitoylation blunted the regulation of K_ATP channels by α1-adrenoreceptor stimulation. The Cys¹⁶⁶ residue is conserved in some other Kir family members (Kir6.1 and Kir3, but not Kir2), which are also subject to regulated palmitoylation, suggesting a general mechanism to control the open state of certain Kir channels.

Impulsivity and stress exposure are two factors that are associated with changes in reward-related behavior in ways that are relevant to both healthy and maladaptive decision-making. Nonetheless, little empirical work has examined the possible independent and joint effects of these factors upon reward learning. Here, we sought to examine how trait impulsivity and acute stress exposure affect participants' choice behavior and decision speed in a two-stage sequential reinforcement-learning task. We found that more impulsive participants were more likely to repeat second-stage choices after previous reward, irrespective of stress condition. Exposure to stress, on the other hand, was associated with an increased tendency to repeat second-stage choices independent of whether these choices previously led to a reward, and this tendency was exacerbated in more impulsive individuals. Such interaction effects between stress and impulsivity were also found on decision speed. Stress and impulsivity levels interacted to drive faster choices overall (again irrespective of reward) at both task stages, while reward received on the previous trial slowed subsequent first-stage choices, particularly among impulsive individuals under stress. Collectively, our results reveal novel, largely interactive effects of trait impulsivity and stress exposure and suggest that stress may reveal individual differences in decision-making tied to impulsivity that are not readily apparent in the absence of stress.

The human serotonin transporter (hSERT) terminates serotonergic signaling through reuptake of neurotransmitter into presynaptic neurons and is a target for many antidepressant drugs. We describe here the development of a photoswitchable hSERT inhibitor, termed azo-escitalopram, that can be reversibly switched between trans and cis configurations using light of different wavelengths. The dark-adapted trans isomer was found to be significantly less active than the cis isomer, formed upon irradiation.

Pain is an integrated sensory and affective experience. Cortical mechanisms of sensory and affective integration, however, remain poorly defined. Here, we investigate the projection from the primary somatosensory cortex (S1), which encodes the sensory pain information, to the anterior cingulate cortex (ACC), a key area for processing pain affect, in freely behaving rats. By using a combination of optogenetics, in vivo electrophysiology, and machine learning analysis, we find that a subset of neurons in the ACC receives S1 inputs, and activation of the S1 axon terminals increases the response to noxious stimuli in ACC neurons. Chronic pain enhances this cortico-cortical connection, as manifested by an increased number of ACC neurons that respond to S1 inputs and the magnified contribution of these neurons to the nociceptive response in the ACC. Furthermore, modulation of this S1→ACC projection regulates aversive responses to pain. Our results thus define a cortical circuit that plays a potentially important role in integrating sensory and affective pain signals.

OBJECTIVES/OBJECTIVE:Cochlear implants (CIs) restore speech perception in quiet but they also eliminate or distort many acoustic cues that are important for music enjoyment. Unfortunately, quantifying music enjoyment by CI users has been difficult because comparisons must rely on their recollection of music before they lost their hearing. Here, we aimed to assess music enjoyment in CI users using a readily interpretable reference based on acoustic hearing. The comparison was done by testing "single-sided deafness" (SSD) patients who have normal hearing (NH) in one ear and a CI in the other ear. The study also aimed to assess binaural musical enjoyment, with the reference being the experience of hearing with a single NH ear. Three experiments assessed the effect of adding different kinds of input to the second ear: electrical, vocoded, or unmodified. DESIGN/METHODS:In experiment 1, music enjoyment in SSD-CI users was investigated using a modified version of the MUSHRA (MUltiple Stimuli with Hidden Reference and Anchor) method. Listeners rated their enjoyment of song segments on a scale of 0 to 200, where 100 represented the enjoyment obtained from a song segment presented to the NH ear, 0 represented a highly degraded version of the same song segment presented to the same ear, and 200 represented enjoyment subjectively rated as twice as good as the 100 reference. Stimuli consisted of acoustic only, electric only, acoustic and electric, as well as other conditions with low pass filtered acoustic stimuli. Acoustic stimulation was provided by headphone to the NH ear and electric stimulation was provided by direct audio input to the subject's speech processor. In experiment 2, the task was repeated using NH listeners who received vocoded stimuli instead of electric stimuli. Experiment 3 tested the effect of adding the same unmodified song segment to the second ear, also in NH listeners. RESULTS:Music presented through the CI only was very unpleasant, with an average rating of 20. Surprisingly, the combination of the unpleasant CI signal in one ear with acoustic stimulation in the other ear was rated more enjoyable (mean = 123) than acoustic processing alone. Presentation of the same monaural musical signal to both ears in NH listeners resulted with even greater enhancement of the experience compared with presentation to a single ear (mean = 159). Repeating the experiment using a vocoder to one ear of NH listeners resulted in interference rather than enhancement. CONCLUSIONS:Music enjoyment from electric stimulation is extremely poor relative to a readily interpretable NH baseline for CI-SSD listeners. However, the combination of this unenjoyable signal presented through a CI and an unmodified acoustic signal presented to a NH (or near-NH) contralateral ear results in enhanced music enjoyment with respect to the acoustic signal alone. Remarkably, this two-ear enhancement experienced by CI-SSD listeners represents a substantial fraction of the two-ear enhancement seen in NH listeners. This unexpected benefit of electroacoustic auditory stimulation will have to be considered in theoretical accounts of music enjoyment and may facilitate the quest to enhance music enjoyment in CI users.