Unpredictable Mixed-Valence Outcomes Induce a Chronic and Reversible Generalized Anxiety-like Phenotype in Male Mice.

Background: Clinical anxiety is a generalized state characterized by feelings of apprehensive expectation and is distinct from momentary responses such as fear or stress. In contrast, most laboratory tests of anxiety focus on acute responses to momentary stressors. Methods: Apprehensive expectation was induced by subjecting mice (for 18 days) to manipulations in which a running response (experiment 1) or a conditioned stimulus (experiment 2) were unpredictably paired with reward (food) or punishment (footshock). Before this treatment, the mice were tested in an open field and light/dark box to assess momentary responses that are asserted to reflect state anxiety. After treatment, the mice were assessed for state anxiety in an elevated plus maze, social interaction test, startle response test, intrusive object burying test, and stress-induced corticosterone elevations. In experiment 3, we treated mice similarly to experiment 1, but after mixed-valence training, some mice received either no additional training, additional mixed-valence training, or were shifted to consistent (predictable) reinforcement with food. Results: We consistently observed an increase in anxiety-like behaviors after the experience with mixed-valence unpredictable reinforcement. This generalized anxiety persisted for at least 4 weeks after the mixed-valence training and could be reversed if the mixed-valence training was followed by predictable reinforcement with food. Conclusions: Results indicate that experience with unpredictable reward/punishment can induce a chronic state analogous to generalized anxiety that can be mitigated by exposure to stable, predictable conditions. This learned apprehension protocol provides a conceptually valid model for the study of the etiology and treatment of anxiety in laboratory animals.

Anxiety disorders have a complex etiology that is difficult to study in laboratory animals because most laboratory manipulations do not induce a chronic, generalized condition analogous to the clinical disorder. Here, laboratory mice developed approach-avoidance conflicts when a response was unpredictably rewarded or punished. These conditions (but not predictable outcomes) promoted a long-lasting general increase in a range of behaviors and stress hormones that reflect underlying anxiety, and remedial exposure to predictable conditions of reward and punishment ameliorated the generalized state. These results represent the development of a conceptually valid animal model for the study of anxiety and suggest conditions that can contribute to the etiology and treatment of anxiety.

The Dorsal Column Nuclei Scale Mechanical Sensitivity in Naive and Neuropathic Pain States.

Tactile perception relies on reliable transmission and modulation of low-threshold information as it travels from the periphery to the brain. During pathological conditions, tactile stimuli can aberrantly engage nociceptive pathways leading to the perception of touch as pain, known as mechanical allodynia. Two main drivers of peripheral tactile information, low-threshold mechanoreceptors (LTMRs) and postsynaptic dorsal column neurons (PSDCs), terminate in the brainstem dorsal column nuclei (DCN). Activity within the DRG, spinal cord, and DCN have all been implicated in mediating allodynia, yet the DCN remains understudied at the cellular, circuit, and functional levels compared to the other two. Here, we show that the gracile nucleus (Gr) of the DCN mediates tactile sensitivity for low-threshold stimuli and contributes to mechanical allodynia during neuropathic pain in mice. We found that the Gr contains local inhibitory interneurons in addition to thalamus-projecting neurons, which are differentially innervated by primary afferents and spinal inputs. Functional manipulations of these distinct Gr neuronal populations resulted in bidirectional changes to tactile sensitivity, but did not affect noxious mechanical or thermal sensitivity. During neuropathic pain, silencing Gr projection neurons or activating Gr inhibitory neurons was able to reduce tactile hypersensitivity, and enhancing inhibition was able to ameliorate paw withdrawal signatures of neuropathic pain, like shaking. Collectively, these results suggest that the Gr plays a specific role in mediating hypersensitivity to low-threshold, innocuous mechanical stimuli during neuropathic pain, and that Gr activity contributes to affective, pain-associated phenotypes of mechanical allodynia. Therefore, these brainstem circuits work in tandem with traditional spinal circuits underlying allodynia, resulting in enhanced signaling of tactile stimuli in the brain during neuropathic pain.

Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn.

Sensory feedback is integral for contextually appropriate motor output, yet the neural circuits responsible remain elusive. Here, we pinpoint the medial deep dorsal horn of the mouse spinal cord as a convergence point for proprioceptive and cutaneous input. Within this region, we identify a population of tonically active glycinergic inhibitory neurons expressing parvalbumin. Using anatomy and electrophysiology, we demonstrate that deep dorsal horn parvalbumin-expressing interneuron (dPV) activity is shaped by convergent proprioceptive, cutaneous, and descending input. Selectively targeting spinal dPVs, we reveal their widespread ipsilateral inhibition onto pre-motor and motor networks and demonstrate their role in gating sensory-evoked muscle activity using electromyography (EMG) recordings. dPV ablation altered limb kinematics and step-cycle timing during treadmill locomotion and reduced the transitions between sub-movements during spontaneous behavior. These findings reveal a circuit basis by which sensory convergence onto dorsal horn inhibitory neurons modulates motor output to facilitate smooth movement and context-appropriate transitions.

Negative attributes of mixed-valence memories strengthen over long retention intervals and the degree of enhancement is predicted by individual differences in state anxiety.

Memories are multifaceted and can simultaneously contain positive and negative attributes. Here, we report that negative attributes of a mixed-valence memory dominate long-term recall. To induce a mixed-valence memory, running responses were randomly reinforced with either food (∼83% of trials) or footshock (∼17% of trials), or a noise conditioned stimulus (CS) was followed randomly with either food (∼80% of trials) or footshock (∼20% of trials). Control animals were consistently reinforced with only food. Mixed-valence training promoted unstable behavior (e.g., erratic approach and withdrawal from the food cup) and moderate levels of fear during the training regimens. After a 20-day retention interval, animals that were consistently reinforced with food exhibited intact approach responding, and similar responding was observed if animals were food deprived or satiated (i.e., the response was insensitive to motivation). However, animals that experienced the mixed-valence training expressed significantly enhanced and stable fear (consistent immobility) relative to the end of training, regardless of whether animals were food deprived or not, suggesting that fear transitioned to a state that was insensitive to motivation. The degree of fear expressed during long-term retention was predicted by measures of state anxiety obtained prior to the training, indicating that the enhancement of fear across the retention interval was related to individual differences in basal "anxiety." These results suggest that negative attributes of memories dominate long-term recall, particularly in animals expressing an anxious phenotype, and these observations have direct implications for the chronic nature of anxiety disorders and the exacerbation of fear that accompanies posttraumatic stress disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Novel Picture Guide to Improve Spiritual Care and Reduce Anxiety in Mechanically Ventilated Adults in the Intensive Care Unit.

RATIONALE: Hospital chaplains provide spiritual care that helps patients facing serious illness cope with their symptoms and prognosis, yet because mechanically ventilated patients cannot speak, spiritual care of these patients has been limited. OBJECTIVES: To determine the feasibility and measure the effects of chaplain-led picture-guided spiritual care for mechanically ventilated adults in the intensive care unit (ICU). METHODS: We conducted a quasi-experimental study at a tertiary care hospital between March 2014 and July 2015. Fifty mechanically ventilated adults in medical or surgical ICUs without delirium or dementia received spiritual care by a hospital chaplain using an illustrated communication card to assess their spiritual affiliations, emotions, and needs and were followed until hospital discharge. Feasibility was assessed as the proportion of participants able to identify spiritual affiliations, emotions, and needs using the card. Among the first 25 participants, we performed semistructured interviews with 8 ICU survivors to identify how spiritual care helped them. For the subsequent 25 participants, we measured anxiety (on 100-mm visual analog scales [VAS]) immediately before and after the first chaplain visit, and we performed semistructured interviews with 18 ICU survivors with added measurements of pain and stress (on ±100-mm VAS). MEASUREMENTS AND MAIN RESULTS: The mean (SD) age was 59 (±16) years, median mechanical ventilation days was 19.5 (interquartile range, 7-29 d), and 15 (30%) died in-hospital. Using the card, 50 (100%) identified a spiritual affiliation, 47 (94%) identified one or more emotions, 45 (90%) rated their spiritual pain, and 36 (72%) selected a chaplain intervention. Anxiety after the first visit decreased 31% (mean score change, -20; 95% confidence interval, -33 to -7). Among 28 ICU survivors, 26 (93%) remembered the intervention and underwent semistructured interviews, of whom 81% felt more capable of dealing with their hospitalization and 0% felt worse. The 18 ICU survivors who underwent additional VAS testing during semistructured follow-up interviews reported a 49-point reduction in stress (95% confidence interval, -72 to -24) and no significant change in physical pain that they attributed to picture-guided spiritual care. CONCLUSIONS: Chaplain-led picture-guided spiritual care is feasible among mechanically ventilated adults and shows potential for reducing anxiety during and stress after an ICU admission.

The implementation of an early rehabilitation program is associated with reduced length of stay: A multi-ICU study.

INTRODUCTION: Survivors of critical illness face many potential long-term sequelae. Prior studies showed that early rehabilitation in the intensive care unit (ICU) reduces physical impairment and decreases ICU and hospital length of stay (LOS). However, these studies are based on a single ICU or were conducted with a small subset of all ICU patients. We examined the effect of an early rehabilitation program concurrently implemented in multiple ICUs on ICU and hospital LOS. METHODS: An early rehabilitation program was systematically implemented in five ICUs at the sites of two affiliated academic institutions. We retrospectively compared ICU and hospital LOS in the year before (1/2011-12/2011) and after (1/2012-12/2012) implementation. RESULTS: In the pre- and post-implementation periods, respectively, there were a total of 3945 and 4200 ICU admissions among the five ICUs. After implementation, there was a significant increase in the proportion of patients who received more rehabilitation treatments during their ICU stay (p < 0.001). The mean number of rehabilitation treatments per ICU patient-day increased from 0.16 to 0.72 (p < 0.001). In the post-implementation period, four of the five ICUs had a statistically significant decrease in mean ICU LOS among all patients. The overall decrease in mean ICU LOS across all five ICUs was 0.4 days (6.9%) (5.8 versus 5.4 days, p < 0.001). Across all five ICUs, there were 255 (6.5%) more admissions in the post-implementation period. The mean hospital LOS for patients from the five ICUs also decreased by 5.4% (14.7 vs. 13.9 days, p < 0.001). CONCLUSIONS: A multi-ICU, coordinated implementation of an early rehabilitation program markedly increased rehabilitation treatments in the ICU and was associated with reduced ICU and hospital LOS as well as increased ICU admissions.