Tone Responses Research Articles

Vascular reactivity stimulated by TMA and TMAO: Are perivascular adipose tissue and endothelium involved?

Trimethylamine (TMA), formed by intestinal microbiota, and its Flavin-Monooxygenase 3 (FMO3) product Trimethylamine-N-Oxide (TMAO), are potential modulators of host cardiometabolic phenotypes. High circulating levels of TMAO are associated with increased risk for cardiovascular diseases. We hypothesized that TMA/TMAO could directly change the vascular tone. Perivascular adipose tissue (PVAT) helps to regulate vascular homeostasis and may also possess FMO3. Thoracic aorta with(+) or without(-) PVAT, also + or - the endothelium (E), of male Sprague Dawley rats were isolated for measurement of isometric tone in response to TMA/TMAO (1nM–0.5 M). Immunohistochemistry (IHC) studies were done to identify the presence of FMO3. TMA and TMAO elicited concentration-dependent arterial contraction. However, at a maximally achievable concentration (0.2 M), contraction stimulated by TMA was of a greater magnitude (141.5 ± 16% of maximum phenylephrine contraction) than that elicited by TMAO (19.1 ± 4.03%) with PVAT and endothelium intact. When PVAT was preserved, TMAO-induced contraction was extensively reduced the presence (19.1 ± 4.03%) versus absence of E (147.2 ± 20.5%), indicating that the endothelium plays a protective role against TMAO-induced contraction. FMO3 enzyme was present in aortic PVAT, but the FMO3 inhibitor methimazole did not affect contraction stimulated by TMA in aorta + PVAT. However, the l-type calcium channel blocker nifedipine reduced TMA-induced contraction by ∼50% compared to the vehicle. Though a high concentration of these compounds was needed to achieve contraction, the findings that TMA-induced contraction was independent of PVAT and E and mediated by nifedipine-sensitive calcium channels suggest metabolite-induced contraction may be physiologically important.

Divergent projections of the prelimbic cortex bidirectionally regulate active avoidance.

The prefrontal cortex (PFC) integrates incoming information to guide our actions. When motivation for food-seeking competes with avoidance of danger, the PFC likely plays a role in selecting the optimal choice. In platform-mediated active avoidance, rats avoid a tone-signaled footshock by stepping onto a nearby platform, delaying access to sucrose pellets. This avoidance requires prelimbic (PL) PFC, basolateral amygdala (BLA), and ventral striatum (VS). We previously showed that inhibitory tone responses of PL neurons correlate with avoidability of shock (Diehl et al., 2018). Here, we optogenetically modulated PL terminals in VS and BLA to identify PL outputs regulating avoidance. Photoactivating PL-VS projections reduced avoidance, whereas photoactivating PL-BLA projections increased avoidance. Moreover, photosilencing PL-BLA or BLA-VS projections reduced avoidance, suggesting that VS receives opposing inputs from PL and BLA. Bidirectional modulation of avoidance by PL projections to VS and BLA enables the animal to make appropriate decisions when faced with competing drives.

EVEN IN THE BEST-CASE SCENARIO L2 LEARNERS HAVE PERSISTENT DIFFICULTY PERCEIVING AND UTILIZING TONES IN MANDARIN

AbstractLexical tones are widely believed to be a formidable learning challenge for adult speakers of nontonal languages. While difficulties—as well as rapid improvements—are well documented for beginning second language (L2) learners, research with more advanced learners is needed to understand how tone perception difficulties impact word recognition once learners have a substantial vocabulary. The present study narrows in on difficulties suggested in previous work, which found a dissociation in advanced L2 learners between highly accurate tone identification and largely inaccurate lexical decision for tone words. We investigate a “best-case scenario” for advanced L2 tone word processing by testing performance in nearly ideal listening conditions—with words spoken clearly and in isolation. Under such conditions, do learners still have difficulty in lexical decision for tone words? If so, is it driven by the quality of lexical representations or by L2 processing routines? Advanced L2 and native Chinese listeners made lexical decisions while an electroencephalogram was recorded. Nonwords had a first syllable with either a vowel or tone that differed from that of a common disyllabic word. As a group, L2 learners performed less accurately when tones were manipulated than when vowels were manipulated. Subsequent analyses showed that this was the case even in the subset of items for which learners showed correct and confident tone identification in an offline written vocabulary test. Event-related potential results indicated N400 effects for both nonword conditions in L1, but only vowel N400 effects in L2, with tone responses intermediate between those of real words and vowel nonwords. These results are evidence of the persistent difficulty most L2 learners have in using tones for online word recognition, and indicate it is driven by a confluence of factors related to both L2 lexical representations and processing routines. We suggest that this tone nonword difficulty has real-world implications for learners: It may result in many toneless word representations in their mental lexicons, and is likely to affect the efficiency with which they can learn new tone words.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Traumatic Brain Injury (tbi) Attenuates Arterial Smooth Muscle Vasorelaxation In Pressurized Cerebral Arteries

Maintenance of cerebral blood flow (CBF) is impaired following traumatic brain injury (TBI), increasing the incidence of both ischemic and hemorrhagic events. Vascular tone is controlled by neurogenic, endothelial, and myogenic responses. PURPOSE: This work was designed to specifically determine the extent to which the myogenic response of vascular smooth muscle in the middle cerebral artery (MCA) is altered following TBI. METHODS: TBI was induced by controlled cortical impact (CCI) in 2-month-old male Sprague-Dawley rats. Twenty-four hours following injury or sham surgery, pressurized arterial myography was performed on endothelium-denuded MCA to examine the effect of TBI on smooth muscle-specific vasorelaxation using pharmacologic activators of the adenylyl cyclase (AC)-cAMP-PKA/PKG pathway (10-9M to 10-5M, n=6 at each dose). RESULTS: Myogenic tone was attenuated following TBI (25±1.1% vs. 18±1.2%, n=12; p<0.001). The mean change in myogenic tone in response to activators (10-6M) was reduced to 35% (AC), 33% (PKA), and 30% (PKG) in TBI as compared to sham controls. CONCLUSION: Attenuation of smooth muscle myogenic tone and resulting vasorelaxation following TBI may serve as a compensatory mechanism to protect sensitive brain tissue from cerebral ischemia. Future work will be needed to elucidate the role of pathways that could serve as potential targets for therapeutic intervention to reduce damaging vascular events. Supported by The Florida State University Graduate School Dissertation Award Grant.

Interhemispheric Callosal Projections Sharpen Frequency Tuning and Enforce Response Fidelity in Primary Auditory Cortex.

Sensory cortical areas receive glutamatergic callosal projections that link information processing between brain hemispheres. In primary auditory cortex (A1), ipsilateral principal cells from a particular tonotopic region project to neurons in matching frequency space of the contralateral cortex. However, the role of interhemispheric projections in shaping cortical responses to sound and frequency tuning in awake animals is unclear. Here, we use translaminar single-unit recordings and optogenetic approaches to probe how callosal inputs modulate spontaneous and tone-evoked activity in A1 of awake mice. Brief activation of callosal inputs drove either short-latency increases or decreases in firing of individual neurons. Across all cortical layers, the majority of responsive regular spiking (RS) cells received short-latency inhibition, whereas fast spiking (FS) cells were almost exclusively excited. Consistent with the callosal-evoked increases in FS cell activity in vivo, brain slice recordings confirmed that parvalbumin (PV)-expressing cells received stronger callosal input than pyramidal cells or other interneuron subtypes. Acute in vivo silencing of the contralateral cortex generally increased spontaneous firing across cortical layers and linearly transformed responses to pure tones via both divisive and additive operations. The net effect was a decrease in signal-to-noise ratio for evoked responses and a broadening of frequency tuning curves. Together, these results suggest that callosal input regulates both the salience and tuning sharpness of tone responses in A1 via PV cell-mediated feedforward inhibition.

Associations among neurophysiology measures in irritable bowel syndrome (IBS) and their relevance for IBS symptoms

Abnormal gut-brain interactions are common in irritable bowel syndrome (IBS), but the associations between neurophysiological measures and their relation to gastrointestinal (GI) symptoms are poorly understood. Our aim was to explore these relationships and define the most relevant neurophysiology measures for GI symptom severity in IBS. IBS patients underwent small intestinal motility (manometry; fasted and fed contraction frequency, phase III time) and secretion (transmural potential difference), rectal sensorimotor (barostat; sensory thresholds, tone response, compliance), autonomic nervous system (baroreceptor sensitivity and effectiveness), and colonic motor function (transit time) examinations. GI symptom severity (GSRS-IBS), and anxiety and depression (HAD) as a proxy measure of central nervous system (CNS) dysfunction, were assessed. In total 281 IBS patients (Rome II criteria) were included (74% females, median age 36 [interquartile range 28–50] years). Significant correlations between neurophysiology measures were stronger within, rather than between, different neurophysiological examinations. The strongest neurophysiology-symptom correlations occurred between a combination of CNS and visceral sensitivity parameters, and GSRS-IBS total score and pain domain (ρ = 0.40, p < 0.001, and ρ = 0.38, p < 0.001). Associations between GI symptoms in IBS and individual and combinations of neurophysiological factors occurred, primarily in CNS and visceral sensitivity measures, providing new insights into the clinical presentation of IBS.

Functional Diagnostics of Arterial Vessels by Pulse Wave Analysis and Equipment for Its Implementation

The results of screening of the arterial system based on pulse waveform measurement by the oscillometric method are presented. Tests were performed in a group of students from the Saratov State National Research University. The muscle tone response to the occlusion of the brachial artery was studied to assess endothelial dysfunction. Of the 71 subjects examined, 65 subjects (92%) responded to the artery occlusion with an increase in the parameter P3 proportional to the second time derivative of the pulse waveform. Six subjects (8%) responded to the artery occlusion with a decrease in P3 indicative of endothelial dysfunction. The test results were confirmed using the duplex ultrasonography screening of the arteries of the upper limbs. The equipment used to implement the suggested diagnostic technique is described.

Female Mice Are Resistant to Inward Remodeling of Parenchymal Arterioles Observed in Male Mice During Angiotensin II‐Induced Hypertension

Hypertension increases risk of vascular cognitive impairment and dementia (VCID) by impairing the structure and function of cerebral arteries. These arterial changes result in chronic hypoperfusion of the brain parenchyma and, eventually, cognitive impairment. Epidemiological studies suggest a sex difference in development of VCID, with women being protected from its development until late in age. We have previously shown that angiotensin II (AngII)‐hypertension led to inward hypotrophic remodeling and decreased wall stress in the parenchymal arterioles (PAs) of male mice. This PA remodeling in AngII‐hypertension was associated with reduced cerebral perfusion, increased myogenic tone, and cognitive dysfunction. Female mice, however, were protected from memory impairments despite a similar increase in blood pressure and decrease in cerebral perfusion measured by scanning laser Doppler. We hypothesized that AngII‐hypertension in female mice will cause a decrease in cerebral perfusion measured by laser speckle contrast, as well as a decrease in outer diameter, lumen diameter, and wall thickness in the PAs. Sixteen to eighteen‐week‐old female C56BL/6 mice were treated with AngII (1200 ng/kg/min via osmotic mini‐pump) for four weeks. This dose was selected to produce a similar increase in blood pressure to the previously studied male mice. Sham mice served as control. Blood pressure was measured by tail‐cuff plethysmography and pial blood flow was measured. After euthanasia, brains were collected and PAs were isolated and mounted on a pressure myograph for assessment of spontaneous myogenic tone generation and structure. PA structure was assessed by increasing intralumenal pressure from 3mmHg to 120mmHg in 20mmHg increments. Results are presented as means ± SEM and PA data are reported at an intralumenal pressure of 40mmHg (n=5–12). Systolic blood pressure was increased (Sham: 141 ± 7, AngII: 179 ± 7mmHg; p&lt;0.05) and cerebral perfusion was reduced in AngII‐hypertension (Sham: 328 ± 6, AngII: 288 ± 11 perfusion units; p&lt;0.05). AngII infusion slightly decreased lumen (Sham: 49 ± 3, AngII: 42 ± 4μm; p=0.17) and outer (Sham: 57 ± 4, AngII: 48 ± 4μm; p=0.11) diameters, although not significantly. AngII‐hypertension reduced wall thickness (Sham: 4 ± 0.3, AngII: 3 ± 0.2μm; p&lt;0.05) and wall area (Sham: 691 ± 83, AngII: 441 ± 52μm2; p&lt;0.05). PAs from female mice did not show reductions in wall stress (Sham: 241.8 ± 19, AngII: 268 ± 20dynes/cm2; p&gt;0.05) or generate more myogenic tone in response to hypertension (Sham: 27 ± 4, AngII: 22 ± 2%; p&gt;0.05). While AngII‐hypertension resulted in reductions in lumen diameter, outer diameter, wall thickness, and wall stress in the PAs of male mice, PAs of female mice had only reduced wall thickness with modest reductions in lumen and outer diameters. Preliminary data suggest that females may be resistant to inward PA remodeling during AngII‐hypertension, despite similar reductions in cerebral blood flow as male mice. This potential protection of the cerebrovascular structure and myogenic tone generation could explain the absence of cognitive dysfunction in response to hypertension in female mice.Support or Funding Information5T32GM092715‐14

Distinct projections from the prelimbic cortex modulate active avoidance

Avoiding threatening stimuli is a survival mechanism that can become maladaptive when avoidance interferes with other goal‐directed behaviors. For example, when an individual is seeking food, a threatening stimulus may be encountered, leading to an avoidance response, which comes at a cost of obtaining food. To model this behavior, we used an active avoidance task in which food‐restricted rats learn to step onto a platform to avoid a tone‐signaled shock, at the cost of obtaining a sucrose pellet. Activity in prelimbic cortex (PL), basolateral amygdala (BLA), and ventral striatum (VS) are necessary for the expression of platform‐mediated active avoidance (PMA) (Bravo‐Rivera, et. al., 2014), suggesting that these structures form a neural circuit to regulate PMA. We recently reported that inhibitory tone responses in PL signal the avoidability of shock, and opposing these responses using 4Hz photoactivation impaired avoidance (Diehl, et. al., 2018). Here, we want to know if PL inhibition signals downstream structures that are necessary for avoidance (i.e. VS and BLA), using an optogenetic approach. Photoactivating PL‐VS projections using Channelrhodopsin (ChR2) impaired avoidance (eYFP 88% (n=12) vs. ChR2 22% (n=8), p&lt;0.0001), whereas photosilencing PL‐VS projections using Archaerhodopsin (ArchT) had no effect, suggesting that inhibition of this pathway promotes avoidance. Additionally, photoactivating PL‐BLA projections accelerated avoidance (eYFP 75% (n=9) vs. ChR2 88% (n=8), p=0.017), and photosilencing PL‐BLA projections impaired avoidance (eYFP 77% (n=9) vs. ArchT 40% (n=7), p=0.026), suggesting that excitation of this pathway promotes avoidance. Overall, these findings suggest that distinct PL projections have opposing roles in controlling avoidance by driving or suppressing avoidance.Support or Funding InformationThis work was supported by NIH grants R37‐MH058883 and P50‐MH086400 (Conte Center) to GJQ; F32‐MH105185 to MMD; 5T34‐GM00782140 to GRB, 5R25‐GM097635 to JIG and VVV; 5R25‐GM061151 to GRB, FDG and JMS.

Dynamics and Hierarchical Encoding of Non-compact Acoustic Categories in Auditory and Frontal Cortex.

Categorical perception is a fundamental cognitive function enabling animals to flexibly assign sounds into behaviorally relevant categories. This study investigates the nature of acoustic category representations, their emergence in an ascending series of ferret auditory and frontal cortical fields, and the dynamics of this representation during passive listening to task-relevant stimuli and during active retrieval from memory while engaging in learned categorization tasks. Ferrets were trained on two auditory Go-NoGo categorization tasks to discriminate two non-compact sound categories (composed of tones or amplitude-modulated noise). Neuronal responses became progressively more categorical in higher cortical fields, especially during task performance. The dynamics of the categorical responses exhibited a cascading top-down modulation pattern that began earliest in the frontal cortex and subsequently flowed downstream to the secondary auditory cortex, followed by the primary auditory cortex. In a subpopulation of neurons, categorical responses persisted even during the passive listening condition, demonstrating memory for task categories and their enhanced categorical boundaries.

Structure and Dynamics of Adrenomedullin Receptors AM1 and AM2 Reveal Key Mechanisms in the Control of Receptor Phenotype by Receptor Activity-Modifying Proteins.

Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal lymphatic and blood vascular development and angiogenesis. They play a pivotal role in embryo implantation and fertility and can provide protection against hypoxic and oxidative stress. CGRP and AM receptors are heterodimers of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) (CGRPR), as well as RAMP2 or RAMP3 (AM1R and AM2R, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AM1R in complex with AM and Gs at a global resolution of 3.0 Å, and structures of the AM2R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 Å, respectively. The structures reveal distinctions in the primary orientation of the extracellular domains (ECDs) relative to the receptor core and distinct positioning of extracellular loop 3 (ECL3) that are receptor-dependent. Analysis of dynamic data present in the cryo-EM micrographs revealed additional distinctions in the extent of mobility of the ECDs. Chimeric exchange of the linker region of the RAMPs connecting the TM helix and the ECD supports a role for this segment in controlling receptor phenotype. Moreover, a subset of the motions of the ECD appeared coordinated with motions of the G protein relative to the receptor core, suggesting that receptor ECD dynamics could influence G protein interactions. This work provides fundamental advances in our understanding of GPCR function and how this can be allosterically modulated by accessory proteins.

Pulling the Hood off Genetic Susceptibility to Hypertensive Renal Disease

Pulling the Hood off Genetic Susceptibility to Hypertensive Renal Disease

TRANSPLANT CORONARY ARTERY VASOSPASM: AN UNDER-RECOGNIZED CLINICAL SYNDROME

Coronary artery vasospasm (CVS) is a relatively rare, under-recognized phenomenon in the setting of orthotopic heart transplantation (OHT). It is hypothesized that the transplanted heart undergoes heterogeneous re-innervation and has altered vasomotor tone in response to cholinergic and

Analysis of endothelial dysfunction in the context of pleural effusions of various origins using skin thermometry

To analyze the mechanisms and severity of endothelial dysfunction in patients with pleural effusion of various origins using skin thermometry. We studied microcirculation in 135 patients with pleural effusions of various origins. Local skin thermometry and computer wavelet analysis were performed in 3-5 days after thoracoscopy with pleural biopsy using Microtest-100WF device with a temperature measuring resolution of 0.001°C. We estimated endothelial, myogenic and neurogenic indices using spectral analysis of skin temperature fluctuations in a range 0.0095-2 Hz. The control group comprised 40 healthy participants aged 23-36 years. Three groups of patients were distinguished depending on the cause of effusion: malignant pleural effusions (n=65, 48.1%); inflammatory pleural effusions (para-pneumonic, post-traumatic, pancreatogenic, tuberculous) (n=58, 43%); transudates (hepatogenic, cardiogenic, and nephrogenic) (n=12, 8.9%). There were no significant differences in vascular tone in response to local heating of the second finger of the hand up to 40°C. Measurements were carried out within 10 min in all groups. Patients with diabetes mellitus and cardiovascular diseases (n=48, 35.6%) had significant decrease of thermal vasodilation index in endothelial range up to 2.93±1.77, in the control group - up to 4.21±2.40 (p=0.041). Endothelial dysfunction is a universal non-specific aspect in pathogenesis of various diseases. This process is essential in pleural effusion. Local thermometry and computer wavelet analysis revealed no significant differences between patients with malignant, inflammatory and transudative pleural effusions. Pleural effusions in the context of cardiovascular pathology and/or diabetes mellitus occur due to impaired vasodilatation mechanisms in endothelial range.

Mind-Body and Psychosocial Interventions May Similarly Affect Heart Rate Variability Patterns in Cancer Recovery: Implications for a Mechanism of Symptom Improvement.

Background:Advancements in early detection and treatment of cancer have led to increased survival rates and greater need to identify effective supportive care options for resolving symptoms of survivorship. Many non-pharmacological approaches to symptom management during and after cancer treatment involve emotional self-regulation as a central strategy for improving well-being. Identifying commonalities among these strategies’ mechanisms of action may facilitate understanding of what might be useful for optimizing intervention effects. Heart rate variability (HRV) parameters are indicative of improved autonomic nervous system (ANS) balance and resiliency and reduced emotional distress and are thus identified as a mechanism to discuss as a marker of potential for intervention efficacy and a target for optimization.Methods:HRV data from 2 studies, 1 examining a mind-body intervention and 1 examining a psychosocial intervention, are presented as a point of discussion about preliminary associations between the interventions, change in HRV, and emotional distress reduction.Results:HRV significantly decreased in sympathetic activity in response to a mind-body intervention (Qigong/Tai Chi), and increased vagal tone in response to a psychosocial (storytelling) intervention. In both, these changes in HRV parameters were associated with improved emotional states.Conclusion:Our preliminary data suggest that HRV may serve as an important marker of underlying changes that mediate emotional regulation; this observation deserves further investigation. If identified as a worthy target, focusing on interventions that improve HRV within the context of interventions for cancer patients may be important to key outcomes and clinical practice.

An Emergent Discriminative Learning Is Elicited During Multifrequency Testing.

In auditory-conditioned fear learning, the freezing response is independent of the sound frequencies used, but the frequency of the conditioned sound is considered distinct from those of unrelated sounds based on electrophysiological responses in the auditory system. Whether an emergent discriminative learning underlies auditory fear conditioning and which nuclei and pathways are involved in it remain unclear. Using behavioral and electrophysiological assays, we found that the response of medial prefrontal cortex (mPFC) neurons to a conditioned auditory stimulus (CS) was enhanced relative to the response to unrelated frequencies (UFs) after auditory fear conditioning, and mice could distinguish the CS during multifrequency testing, a phenomenon called emergent discriminative learning. After silencing the mPFC with muscimol, emergent discriminative learning was blocked. In addition, the pure tone responses of mPFC neurons were inhibited after injection of lidocaine in the ipsilateral primary auditory cortex (A1), and the emergent discriminative learning was blocked by silencing both sides of A1 with muscimol. This study, therefore, provides evidence for an emergent discriminative learning mediated by mPFC and A1 neurons after auditory fear conditioning.

Heart rate variability in adults with obstructive sleep apnea: a systematic review.

Obstructive Sleep Apnea is a common respiratory disorder characterized by recurrent nocturnal episodes of normal breathing interruption due to upper airway total or partial collapse. Obstructive sleep apnea and cardiovascular diseases has similar risk factors, but the first is also a predisposing factor for cardiovascular pathologies independently of individuals demographic characteristics or risk markers. Heart rate variability is a non-invasive method to evaluate the regulation of autonomic nervous system and its a promising marker for health and disease, such as cardiovascular and respiratory diseases. The aim was to review whether heart rate variability is altered in patients with obstructive sleep apnea. We searched in five databases, including BIREME, Cochrane, Scholar Google, MEDLINE/PubMed and Periodics CAPES, and reference lists were also searched. Only cross-sectional studies comparing the heart rate variability of obstructive sleep patients with controls were included. Two authors independently extracted data and assessed trial quality. Twelve studies (513 participants with obstructive sleep apnea and 340 controls) met the inclusion criteria. This review evidence that adults with obstructive sleep apnea may demonstrate diminished vagal tone and higher sympathetic responsiveness.

Cardiac vagal tone, plasma cortisol, and dehydroepiandrosterone response to an ACTH challenge in lame and nonlame dairy cows

We studied the adrenocortical and vagal tone responses to a single ACTH challenge in lame (n = 9) vs nonlame (n = 9) dairy cows. Cows were paired according to parity, days in milk, and milk yield. Plasma cortisol and dehydroepiandrosterone concentrations and cardiac vagal tone response (high-frequency component of heart rate variability) were compared after intravenous ACTH administration. Baseline, minimum or maximum, amplitude of the response and area under the response curve were compared. No difference was detected between groups in the cortisol response. Dehydroepiandrosterone was irresponsive to ACTH treatment, and concentrations did not differ between lame and nonlame cows. Vagal tone decreased in response to the ACTH treatment. High frequency component of heart rate variability was lower in the lame group at all sampling times. Lameness was associated with delayed return to baseline. We concluded that the adrenal response capacity is not influenced by lameness, which supports the concept of lameness being a chronic intermittent rather than a chronically persistent stressor. Dehydroepiandrosterone concentrations were not proven to be useful indicators of hypothalamus–pituitary axis dysfunction in cattle. A decreased vagal contribution to heart rate variability—possibly coupled with increased sympathetic modulation—was observed in lame cows, which suggests that lameness affects the mechanisms underlying the action of ACTH on cardiovascular activity.

Modeling Interval Timing by Recurrent Neural Nets.

The purpose of this study was to take a new approach in showing how the central nervous system might encode time at the supra-second level using recurrent neural nets (RNNs). This approach utilizes units with a delayed feedback, whose feedback weight determines the temporal properties of specific neurons in the network architecture. When these feedback neurons are coupled, they form a multilayered dynamical system that can be used to model temporal responses to steps of input in multidimensional systems. The timing network was implemented using separate recurrent “Go” and “No-Go” neural processing units to process an individual stimulus indicating the time of reward availability. Outputs from these distinct units on each time step are converted to a pulse reflecting a weighted sum of the separate Go and No-Go signals. This output pulse then drives an integrator unit, whose feedback weight and input weights shape the pulse distribution. This system was used to model empirical data from rodents performing in an instrumental “peak interval timing” task for two stimuli, Tone and Flash. For each of these stimuli, reward availability was signaled after different times from stimulus onset during training. Rodent performance was assessed on non-rewarded trials, following training, with each stimulus tested individually and simultaneously in a stimulus compound. The associated weights in the Go/No-Go network were trained using experimental data showing the mean distribution of bar press rates across an 80 s period in which a tone stimulus signaled reward after 5 s and a flash stimulus after 30 s from stimulus onset. Different Go/No-Go systems were used for each stimulus, but the weighted output of each fed into a final recurrent integrator unit, whose weights were unmodifiable. The recurrent neural net (RNN) model was implemented using Matlab and Matlab’s machine learning tools were utilized to train the network using the data from non-rewarded trials. The neural net output accurately fit the temporal distribution of tone and flash-initiated bar press data. Furthermore, a “Temporal Averaging” effect was also obtained when the flash and tone stimuli were combined. These results indicated that the system combining tone and flash responses were not superposed as in a linear system, but that there was a non-linearity, which interacted between tone and flash. In order to achieve an accurate fit to the empirical averaging data it was necessary to implement non-linear “saliency functions” that limited the output signal of each stimulus to the final integrator when the other was co-present. The model suggests that the central nervous system encodes timing generation as a dynamical system whose timing properties are embedded in the connection weights of the system. In this way, event timing is coded similar to the way other sensory-motor systems, such as the vestibulo-ocular and optokinetic systems, which combine sensory inputs from the vestibular and visual systems to generate the temporal aspects of compensatory eye movements.