Awake Animals Research Articles

Supraspinal Opioid Circuits Differentially Modulate Spinal Neuronal Responses in Neuropathic Rats.

The anterior cingulate cortex and central nucleus of the amygdala connect widely with brainstem nuclei involved in descending modulation, including the rostral ventromedial medulla. Endogenous opioids in these circuits participate in pain modulation. The hypothesis was that a differential opioidergic role for the brain nuclei listed in regulation of spinal neuronal responses because separable effects on pain behaviors in awake animals were previously observed. This study utilized in vivo electrophysiology to determine the effects of morphine microinjection into the anterior cingulate cortex, right or left central nucleus of the amygdala, or the rostral ventromedial medulla on spinal wide dynamic range neuronal responses in isoflurane-anesthetized, male Sprague-Dawley rats. Ongoing activity in the ventrobasal thalamus was also measured. In total, 33 spinal nerve ligated and 26 control age- and weight-matched control rats were used. Brainstem morphine reduced neuronal firing to 60-g von Frey stimulation in control rats (to 65 ± 12% of control response (means ± 95% CI), P < 0.001) with a greater inhibition in neuropathic rats (to 53 ± 17% of control response, P < 0.001). Contrasting anterior cingulate cortex morphine had only marginal modulatory effects on spinal neuronal responses with limited variance in effect between control and neuropathic rats. The inhibitory effects of morphine in the central nucleus of the amygdala were dependent on pain state and laterality; only right-side morphine reduced neuronal firing to 60-g stimulation in neuropathic rats (to 65 ± 14% of control response, P = 0.001). In addition, in neuropathic rats elevated ongoing neuronal activity in the ventral posterolateral thalamus was not inhibited by anterior cingulate cortex morphine, in contrast to evoked responses. Cumulatively the data support opioid modulation of evoked responses predominately through a lateralized output from the right amygdala, as well as from the brainstem that is enhanced in injured conditions. Minimal modulation of dorsal horn responses was observed after anterior cingulate cortex opioid administration regardless of injury state.

Effects of exercise training on metabolic and cardiovascular dysfunctions in offspring of fructose animals: role of cholinergic anti‐inflammatory reflex.

AimTo evaluate the effects of aerobic ET on metabolic and cardiovascular parameters in offspring of fructose‐consuming animals, testing the role of cholinergic anti‐inflammatory reflex in this condition by splenectomy.MethodsOffspring of Wistar genitor rats treated with fructose or placebo (water) were divided into 4 groups: sedentary‐water (W), sedentary‐fructose (F), trained‐fructose (TF) and trained‐splenectomized‐fructose (TSF). Fructose overload (10%) was started 30 days after weaning only for the parents and continued until the end of lactation. The offspring received standard feeding and 30 days after weaning the spleen was removed (splenectomy) and the ET was started on treadmill (1h/d, 5d/week, 4 weeks, moderate intensity). After 30 days, the glycemia, blood triglycerides (TG) and insulin tolerance were evaluated. Blood pressure (BP) and heart rate (HR) signals were directly recorded in awake animals through an acquisition system.ResultsAlthough no differences in glycemia and insulin tolerance were observed, the TSF group showed an increase in TG compared to W, F and TF groups (166 ± 12 vs. 100±6; 113±11; 110±4 mg/dL). Regarding cardiovascular changes, the F group had increased systolic blood pressure (SBP) compared to W group (F: 127±4 vs. W: 117±2 mmHg). ET prevented the increase in SBP (TF: 118 ± 2 mmHg); however, this benefit was not observed in the TSF group (129±5 mmHg). In addition, diastolic BP was higher in the TSF group (100±6 mmHg) compared to W and TF groups (91 ± 3 and 87 ± 2 mmHg). There was no difference in HR between the groups studied. BP variability was increased in F group in relation to TSF group.ConclusionThe consumption of fructose by parents induced early BP changes in offspring, which were prevented by exercise training. In addition, splenectomy abolished the cardiovascular benefits of ET in offspring of fructose rats, suggesting participation of the anti‐inflammatory cholinergic reflex in these adaptations.Support or Funding InformationFAPESP: 2018/17183‐4, CNPq (157746/2018‐6) and UNINOVE

Respiratory pattern and phrenic and hypoglossal nerve activity during normoxia and hypoxia in 6-OHDA-induced bilateral model of Parkinson\u2019s disease

Respiratory disturbances present in Parkinson’s disease (PD) are not well understood. Thus, studies in animal models aimed to link brain dopamine (DA) deficits with respiratory impairment are needed. Adult Wistar rats were lesioned with injection of 6-hydroxydopamine (6-OHDA) into the third cerebral ventricle. Two weeks after hypoxic test was performed in whole-body plethysmography chamber, phrenic (PHR) and hypoglossal (HG) nerve activities were recorded in normoxic and hypoxic conditions in anesthetized, vagotomized, paralyzed and mechanically ventilated rats. The effects of activation and blockade of dopaminergic carotid body receptors were investigated during normoxia in anesthetized spontaneously breathing rats. 6-OHDA injection affected resting respiratory pattern in awake animals: an increase in tidal volume and a decrease in respiratory rate had no effect on minute ventilation. Hypoxia magnified the amplitude and minute activity of the PHR and HG nerve of 6-OHDA rats. The ratio of pre-inspiratory to inspiratory HG burst amplitude was reduced in normoxic breathing. Yet, the ratio of pre-inspiratory time to total time of the respiratory cycle was increased during normoxia. 6-OHDA lesion had no impact on DA and domperidone effects on the respiratory pattern, which indicate that peripheral DA receptors are not affected in this model. Analysis of monoamines confirmed substantial striatal depletion of dopamine, serotonin and noradrenaline (NA) and reduction of NA content in the brainstem. In bilateral 6-OHDA model changes in activity of both nerves: HG (linked with increased apnea episodes) and PHR are present. Demonstrated respiratory effects could be related to specific depletion of DA and NA.

Activation of the expiratory muscles via lower thoracic high frequency spinal cord stimulation in awake animals

Lower thoracic spinal cord stimulation is an effective method of restoring an effective cough in participants with complete spinal cord injury. The high voltage requirements however significantly limits this application in subjects with intact lower chest wall sensation. In anesthetized animals, we have shown that the expiratory muscles can also be effectively activated with low stimulus currents (1 mA) but with high stimulus frequencies (HF-SCS -500 Hz). In 3 intact, awake pigs the responses to HF-SCS, were evaluated. HF-SCS was associated with marked expansion of the abdominal wall and external oblique EMG activity without any associated changes in heart rate or vocalization. During a terminal procedure under general anesthesia, responses to HF-SCS were re-assessed. Abdominal movement and EMG were similar to that observed in the awake state. HF-SCS (1.5 mA) resulted in an airway pressure of 65 ± 2cmH2O. Our results indicate that lower thoracic HF-SCS may be a useful method to restore an effective cough in patients with intact chest wall sensation.

Early transcranial direct current stimulation treatment exerts neuroprotective effects on 6-OHDA-induced Parkinsonism in rats

BackgroundTranscranial direct current stimulation (tDCS) has been proven to be able to modulate motor cortical plasticity might have potential as an alternative, adjunctive therapy for Parkinson’s disease (PD). However, the efficacy of tDCS in PD is still uncertain. A disease animal model may be useful to clarify the existence of a treatment effect and to explore an effective therapeutic strategy using tDCS protocols. ObjectiveThe current study was designed to identify the comprehensive therapeutic effects of tDCS in 6-hydroxydopamine (6-OHDA)-lesioned PD rats. MethodsFollowing early and long-term tDCS application (starting 24 h after PD lesion, 300 μA anodal tDCS, 20 min/day, 5 days/week) in awake PD animals for a total of 4 weeks, the effects of tDCS on motor and non-motor behaviors as well as dopaminergic neuron degeneration levels, were identified. ResultsWe found that the 4-week tDCS intervention significantly alleviated 6-OHDA-induced motor deficits in locomotor activity, akinesia, gait pattern and anxiety-like behavior, but not in apomorphine-induced rotations, recognition memory and depression-like behavior. Immunohistochemically, tyrosine hydroxylase (TH)-positive neurons in the substantia nigra were significantly preserved in the tDCS intervention group. ConclusionsThese results suggest that early and long-term tDCS could exert neuroprotective effects and reduce the aggravation of motor dysfunctions in a 6-OHDA-induced PD rat model. Furthermore, this preclinical model may enhance the promising possibility of the potential use of tDCS and serve as a translational platform to further identify the therapeutic mechanism of tDCS for PD or other neurological disorders.

Fossorial giant Zambian mole-rats have blunted ventilatory responses to environmental hypoxia and hypercapnia

Fossorial giant Zambian mole-rats are believed to live in a hypoxic and hypercapnic subterranean environment but their physiological responses to these challenges are entirely unknown. To investigate this, we exposed awake and freely-behaving animals to i) 6 h of normoxia, ii) acute graded normocapnic hypoxia (21, 18, 15, 12, 8, and 5% O2, 0% CO2, balance N2; 1 h each), or iii) acute graded normoxic hypercapnia (0, 2, 5, 7, 9, and 10% CO2, 21% O2, balance N2; 1 h each), followed by a 1 h normoxic normocapnic recovery period, while non-invasively measuring ventilation, metabolic rate, and body temperature (Tb). We found that these mole-rats had a blunted hypoxic ventilatory response that manifested at 12% inhaled O2, a robust hypoxic metabolic response (up to a 68% decrease, starting at 15% O2), and decreased Tb (at or below 8% O2). Upon reoxygenation, metabolic rate increased 52% above normoxic levels, suggesting the paying off of an O2 debt. Ventilation was less sensitive to environmental hypercapnia than to environmental hypoxia and animals also exhibited a blunted hypercapnic ventilatory response that did not manifest below 9% inhaled CO2. Conversely, metabolism and Tb were not affected by hypercapnia. Taken together, these results indicate that, like most other fossorial rodents, giant Zambian mole-rats have blunted hypoxic and hypercapnic ventilatory responses and employ metabolic suppression to tolerate acute hypoxia. Blunted physiological responses to hypoxia and hypercapnia likely reflect the subterranean lifestyle of this mammal, wherein intermittent but severe hypoxia and/or hypercapnia may be common challenges.

Maternal Experience-Dependent Cortical Plasticity in Mice Is Circuit- and Stimulus-Specific and Requires MECP2.

The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.

From Neurons to Cognition: Technologies for Precise Recording of Neural Activity Underlying Behavior.

Understanding how brain activity encodes information and controls behavior is a long-standing question in neuroscience. This complex problem requires converging efforts from neuroscience and engineering, including technological solutions to perform high-precision and large-scale recordings of neuronal activity in vivo as well as unbiased methods to reliably measure and quantify behavior. Thanks to advances in genetics, molecular biology, engineering, and neuroscience, in recent decades, a variety of optical imaging and electrophysiological approaches for recording neuronal activity in awake animals have been developed and widely applied in the field. Moreover, sophisticated computer vision and machine learning algorithms have been developed to analyze animal behavior. In this review, we provide an overview of the current state of technology for neuronal recordings with a focus on optical and electrophysiological methods in rodents. In addition, we discuss areas that future technological development will need to cover in order to further our understanding of the neural activity underlying behavior.

Hindlimb motor responses evoked by microstimulation of the lumbar dorsal root ganglia during quiet standing

Somatosensory afferent pathways have been a target for neural prostheses that seek to restore sensory feedback from amputated limbs and to recruit muscles paralyzed by neurological injury. These pathways supply inputs to spinal reflex circuits that are necessary for coordinating muscle activity in the lower limb. The dorsal root ganglia (DRG) is a potential site for accessing sensory neurons because DRG microstimulation selectively recruits major nerve branches of the cat hindlimb. Previous DRG microstimulation experiments have been performed in anesthetized animals, but effects on muscle recruitment and behavior in awake animals have not been examined. Objective. The objective of the current study was to measure the effects of DRG microstimulation on evoking changes in hindlimb muscle activity during quiet standing. Approach. In this study, 32-channel penetrating microelectrode arrays were implanted chronically in the left L6 and L7 DRG of four cats. During each week of testing, one DRG electrode was selected to deliver microstimulation pulse-trains during quiet standing. Electromyographic (EMG) signals were recorded from intramuscular electrodes in ten hindlimb muscles, and ground-reaction forces (GRF) were measured under the foot of the implanted limb. Main results. DRG Microstimulation evoked a mix of excitatory and inhibitory responses across muscles. Response rates were highest when microstimulation was applied on the L7 array, producing more excitatory than inhibitory responses. Response rates for the L6 array were lower, and the composition of responses was more evenly balanced between excitation and inhibition. On approximately one third of testing weeks, microstimulation induced a transient unloading of the hindlimb as indicated by a decrease in GRF. Reciprocal inhibition at the knee was a prevalent response pattern across testing days which contributed to the unloading force on this subset of testing weeks. Significance. Results show that single-channel microstimulation in the lumbar DRG evokes stereotyped patterns of muscle recruitment in awake animals, demonstrating that even limited sensory input can elicit hindlimb behavior. These findings imply that DRG microstimulation may have utility in neural prosthetic applications aimed at restoring somatosensory feedback and promoting motor function after neurological injury.

Bidirectional Optogenetically-Induced Plasticity of Evoked Responses in the Rat Medial Prefrontal Cortex Can Impair or Enhance Cognitive Set-Shifting.

Chronic stress compromises cognition, including executive function mediated in the medial prefrontal cortex (mPFC). To investigate mechanisms underlying these processes, we use chronic unpredictable stress (CUS), which reduces activity in the mPFC and impairs cognitive set-shifting, a measure of cognitive flexibility in laboratory rats. It has been shown that CUS attenuates the local electrical field potential response evoked in the mPFC by stimulation of the ascending excitatory afferent from the mediodorsal thalamus (MDT). Thus, in this study, to investigate the role that such changes in afferent-evoked responsivity of the mPFC might play in the cognitive deficits induced by CUS, we used optogenetics to directly induce plastic changes in the thalamic-mPFC afferent pathway. Glutamatergic neurons in the MDT were virally-induced to express the ChETA variant of channelrhodopsin. Then, to first validate the optogenetic induction of plasticity, long-term depression (LTD) or long-term potentiation (LTP) were induced by laser stimulation of ChETA-expressing terminals in the mPFC of anesthetized rats. In subsequent experiments, induction of opto-LTD in awake animals produced set-shifting deficits similar to those induced by CUS. By contrast, inducing opto-LTP in rats that had received prior CUS treatment corrected the stress-induced deficit in set-shifting. These results suggest that stress-induced plasticity in the thalamic-mPFC pathway is sufficient to produce stress-induced cognitive deficits, and may represent a novel target for effective therapeutic intervention to correct cognitive impairment in stress-related psychiatric disorders.

Imaging the effect of the circadian light–dark cycle on the glymphatic system in awake rats

The glymphatic system functions in the removal of potentially harmful metabolites and proteins from the brain. Dynamic, contrast-enhanced MRI was used in fully awake rats to follow the redistribution of intraventricular contrast agent entrained to the light-dark cycle and its hypothetical relationship to the sleep-waking cycle, blood flow, and brain temperature in specific brain areas. Brain areas involved in circadian timing and sleep-wake rhythms showed the lowest redistribution of contrast agent during the light phase or time of inactivity and sleep in rats. Global brain redistribution of contrast agent was heterogeneous. The redistribution was highest along the dorsal cerebrum and lowest in the midbrain/pons and along the ventral surface of the brain. This heterogeneous redistribution of contrast agent paralleled the gradients and regional variations in brain temperatures reported in the literature for awake animals. Three-dimensional quantitative ultrashort time-to-echo contrast-enhanced imaging was used to reconstruct small, medium, and large arteries and veins in the rat brain and revealed areas of lowest redistribution overlapped with this macrovasculature. This study raises new questions and theoretical considerations of the impact of the light-dark cycle, brain temperature, and blood flow on the function of the glymphatic system.

Dorsal hippocampus cholinergic and nitrergic neurotransmission modulates the cardiac baroreflex function in rats.

Hippocampus is a limbic structure involved in the baroreflex and chemoreflex control that receives extensive cholinergic input from basal forebrain. Hippocampal muscarinic receptors activation by acetylcholine might evoke nitric oxide synthesis, which is an important neuromodulator of cardiovascular responses. Thus, we hypothesize that cholinergic and nitrergic neurotransmission within the DH modulates the baroreflex and chemoreflex function. We have used vasoactive drugs (phenylephrine and sodium nitroprusside), and potassium cyanide infused peripherally to induce, respectively, baroreflex or chemoreflex responses in awake animals. Bilateral injection into the DH of the acetylcholinesterase inhibitor (neostigmine) reduced baroreflex responses. Meanwhile, the non-selective muscarinic receptor antagonist (atropine) or the M1-selective muscarinic receptor antagonist increased baroreflex responses (pirenzepine). Furthermore, the neuronal nitric oxide synthase inhibitor (N-propyl) or the intracellular NO scavenger (carboxy-PTIO) increased baroreflex responses, as well as the selective inhibitor of NO-sensitive guanylyl cyclase (ODQ), increased the baroreflex responses. Besides, bilateral administration of an ineffective dose of a neuronal nitric oxide synthase inhibitor abolished the reduction in the baroreflex responses evoked by an acetylcholinesterase inhibitor. On the other hand, we have demonstrated that hippocampal cholinergic neurotransmission did not influence the chemoreflex function. Taken together, our findings suggest that nNOS-derived nitric oxide in the DH participates in acetylcholine-evoked baroreflex responses.

New Device for Noninvasive Telemetric Monitoring of Vital Signs in Healthy and Newly Operated Piglets.

Measuring vital signs is central to medical practice, but they are difficult to monitor in awake laboratory animals. We examined the feasibility of a noninvasive device for telemetric assessment of respiration rate, heart rate, temperature and movement in pigs. Awake piglets were monitored continuously for 31 h (interquartile range, 7) before (n = 4) and after (n = 3) surgery. Data quality was sufficient for determination of all parameters. We conclude that continuous, noninvasive monitor- ing of pigs is possible by using the evaluated device.

The Cyclitol L-(+)-Bornesitol as an Active Marker for the Cardiovascular Activity of the Brazilian Medicinal Plant Hancornia speciosa.

The cyclitol bornesitol is the main constituent of the leaves from the antihypertensive medicinal plant Hancornia speciosa. This study aimed to investigate the ability of bornesitol to reduce blood pressure and its mechanism of action. Normotensive Wistar rats were divided into control group and bornesitol groups treated intravenously with bornesitol (0.1, 1.0 and 3.0 mg/kg). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in non-anesthetized awake animals. Nitric oxide (NO) and angiotensin-converting enzyme (ACE) were measured in plasma by using colorimetric methods. Vascular reactivity study was performed in rat aorta rings and the involvement of nitric oxide synthase (NOS), calcium-calmodulin complex and phosphatidylinositol-3-kinase (PI3K)/Akt pathway in the vasodilator effect was investigated. Administration of bornesitol significantly reduced the SBP, increased the plasmatic level of nitrite, and decreased ACE activity in normotensive rats. In the rat aorta, bornesitol induced endothelium-dependent vasodilatation, which was abolished by NOS blockade. While calcium-calmodulin complex inhibition decreased the vasodilator effect of bornesitol, the inhibition of PI3K/Akt pathway did not alter it. Bornesitol reduced the blood pressure by a mechanism involving an increased production or bioavailability of NO, inhibition of ACE, and by an endothelium- and NO-dependent vasodilator effect. The present results support the use of bornesitol as an active marker for the cardiovascular activity of Hancornia speciosa.

Matching stimulation paradigms resolve apparent differences between optogenetic and electrical VTA stimulation

BackgroundOptogenetic stimulation has grown into a popular brain stimulation method in basic neuroscience while electrical stimulation predominates in clinical applications. In order to explain the effects of electrical stimulation on a cellular level and evaluate potential advantages of optogenetic therapies, comparisons between the two stimulation modalities are necessary. This comparison is hindered, however, by the difficulty of effectively matching the two fundamentally different modalities. ObjectiveComparison of brain-wide activation patterns in response to intensity-matched electrical and optogenetic VTA stimulation. MethodsWe mapped optogenetic and electrical self-stimulation rates in the same mice over stimulation intensity and determined iso-behavioral intensities. Using functional 99mTc-HMPAO SPECT imaging of cerebral blood flow in awake animals, we obtained brain-wide activation patterns for both modalities at these iso-behavioral intensities. We performed these experiments in two mouse lines commonly used for optogenetic VTA stimulation, DAT::Cre and TH::Cre mice. ResultsWe find iso-behavioral intensity matching of stimulation gives rise to similar brain activation patterns. Differences between mouse lines were more pronounced than differences between modalities. ConclusionsPreviously found large differences of electrical and optogenetic stimulation might be due to unmatched stimulation intensity, particularly relative electrical overstimulation. These findings imply that therapeutic electrical VTA stimulation might be relatively specific if employed with optimized parameters.

Impact of atherosclerotic disease on cerebral microvasculature and tissue oxygenation in awake LDLR−/−hApoB+/+ transgenic mice

.We explore cortical microvasculature changes during the progression of atherosclerosis using young and old transgenic atherosclerotic (ATX) mice with thinned-skull cranial window. In awake animals, exploiting intrinsic signal optical imaging, Doppler optical coherence tomography, and two-photon microscopy, we investigate how the progression of atherosclerotic disease affects the morphology and function of cortical microvasculature as well as baseline cerebral tissue oxygenation. Results show that aged ATX mice exhibited weaker hemodynamic response in the somatosensory cortex to whisker stimulation and that the diameter of their descending arterioles and associated mean blood flow decreased significantly compared with the young ATX group. Data from two-photon phosphorescence lifetime microscopy indicate that old ATX mice had lower and more heterogeneous partial pressure of oxygen () in cortical tissue than young ATX mice. In addition, hypoxic micropockets in cortical tissue were found in old, but not young, ATX mice. Capillary red blood cell (RBC) flux, RBC velocity, RBC velocity heterogeneity, hematocrit, and diameter were also measured using line scans with two-photon fluorescence microscopy. When compared with the young group, RBC flux, velocity, and hematocrit decreased and RBC velocity heterogeneity increased in old ATX mice, presumably due to disturbed blood supply from arterioles that were affected by atherosclerosis. Finally, dilation of capillaries in old ATX mice was observed, which suggests that capillaries play an active role in compensating for an oxygen deficit in brain tissue.

Resting-state fMRI data of awake dogs (Canis familiaris) via group-level independent component analysis reveal multiple, spatially distributed resting-state networks

Resting-state networks are spatially distributed, functionally connected brain regions. Studying these networks gives us information about the large-scale functional organization of the brain and alternations in these networks are considered to play a role in a wide range of neurological conditions and aging. To describe resting-state networks in dogs, we measured 22 awake, unrestrained individuals of both sexes and carried out group-level spatial independent component analysis to explore whole-brain connectivity patterns. In this exploratory study, using resting-state functional magnetic resonance imaging (rs-fMRI), we found several such networks: a network involving prefrontal, anterior cingulate, posterior cingulate and hippocampal regions; sensorimotor (SMN), auditory (AUD), frontal (FRO), cerebellar (CER) and striatal networks. The network containing posterior cingulate regions, similarly to Primates, but unlike previous studies in dogs, showed antero-posterior connectedness with involvement of hippocampal and lateral temporal regions. The results give insight into the resting-state networks of awake animals from a taxon beyond rodents through a non-invasive method.

BDNF downregulates β-adrenergic receptor-mediated hypotensive mechanisms in the paraventricular nucleus of the hypothalamus.

Brain-derived neurotrophic factor (BDNF) is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli such as stress and hyperosmolality, and BDNF acting in the PVN plays a key role in elevating sympathetic activity and blood pressure. However, downstream mechanisms mediating these effects remain unclear. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN. Male Sprague-Dawley rats received bilateral PVN injections of viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of vehicle or anti-dopamine-β-hydroxylase-conjugated saporin (DSAP), a neurotoxin that selectively lesions noradrenergic and adrenergic neurons. BDNF overexpression in the PVN without NTS lesioning significantly increased mean arterial pressure (MAP) in awake animals by 18.7 ± 1.8 mmHg. DSAP treatment also increased MAP in the GFP group, by 9.8 ± 3.2 mmHg, but failed to affect MAP in the BDNF group, indicating a BDNF-induced loss of NTS catecholaminergic hypotensive effects. In addition, in α-chloralose-urethane-anesthetized rats, hypotensive responses to PVN injections of the β-adrenergic agonist isoprenaline were significantly attenuated by BDNF overexpression, whereas PVN injections of phenylephrine had no effect on blood pressure. BDNF treatment was also found to significantly reduce β1-adrenergic receptor mRNA expression in the PVN, whereas expression of other adrenergic receptors was unaffected. In summary, increased BDNF expression in the PVN elevates blood pressure, in part by downregulating β-receptor signaling and diminishing hypotensive catecholaminergic input from the NTS to the PVN.NEW & NOTEWORTHY We have shown that BDNF, a key hypothalamic regulator of blood pressure, disrupts catecholaminergic signaling between the NTS and the PVN by reducing the responsiveness of PVN neurons to inhibitory hypotensive β-adrenergic input from the NTS. This may be occurring partly via BDNF-mediated downregulation of β1-adrenergic receptor expression in the PVN and results in an increase in blood pressure.

High-potency ligands for DREADD imaging and activation in rodents and monkeys

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

Merging motor and sensory

Neuroscience The posterior parietal cortex of the rat's brain is involved in a broad repertoire of behaviors. These range from integration of multiple sensory inputs to organizing the corresponding muscular responses. The function of the various microcircuit components is incompletely understood. Mohan et al. used several techniques to record from neurons in the different layers of the posterior parietal cortex in anesthetized and awake animals. The authors found that different parts of the processing circuits occurred in the different layers. Touch was encoded in layers 2 to 4, whereas exploratory whisker motion was represented in layers 2 to 4 and layer 6, but not in layer 5. These results may help the development of brain-machine interfaces needed to alleviate the effects of spinal cord injury. J. Neurosci. 39 , 7332 (2019).