Yan, JJ;Ding, XJ;He, T;Chen, AX;Zhang, W;Yu, ZX;Cheng, XY;Wei, CY;Hu, QD;Liu, XY;Zhang, YL;He, M;Xie, ZY;Zha, X;Xu, C;Cao, P;Li, H;Xu, XH;
PMID: 36463200 | DOI: 10.1038/s41467-022-35211-7
Behavioral observations suggest a connection between anxiety and predator defense, but the underlying neural mechanisms remain unclear. Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors. By in vivo recordings in male mice, we find that activity of AHN GABAergic (AHNVgat+) neurons shows individually stable increases when animals approach unfamiliar objects in an open field (OF) or when they explore the open-arm of an elevated plus-maze (EPM). Moreover, object-evoked AHN activity overlap with predator cue responses and correlate with the object and open-arm avoidance. Crucially, exploration-triggered optogenetic inhibition of AHNVgat+ neurons reduces object and open-arm avoidance. Furthermore, retrograde viral tracing identifies the ventral subiculum (vSub) of the hippocampal formation as a significant input to AHNVgat+ neurons in driving avoidance behaviors in anxiogenic situations. Thus, convergent activation of AHNVgat+ neurons serves as a shared mechanism between anxiety and predator defense to promote behavioral avoidance.
Sartori, AM;Hofer, AS;Scheuber, MI;Rust, R;Kessler, TM;Schwab, ME;
PMID: 34826427 | DOI: 10.1016/j.expneurol.2021.113937
Neurogenic lower urinary tract dysfunction typically develops after spinal cord injury. We investigated the time course and the anatomical changes in the spinal cord that may be causing lower urinary tract symptoms following injury. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. Animals underwent a large, incomplete spinal transection at the T8/9 spinal level. At 1, 2-3, and 4 weeks after injury, the animals underwent urodynamic investigations. Urodynamic investigations showed detrusor overactivity and detrusor-sphincter-dyssynergia appearing over time at 3-4 weeks after injury. Lower urinary tract dysfunction was accompanied by an increase in density of C-fiber afferents in the lumbosacral dorsal horn. CRF-positive Barrington's and 5-HT-positive bulbospinal projections drastically decreased after injury, with partial compensation for the CRF fibers at 3-4 weeks. Interestingly, a decrease over time was observed in the number of GABAergic neurons in the lumbosacral dorsal horn and lamina X, and a decrease of glutamatergic cells in the dorsal horn. Detrusor overactivity and detrusor-sphincter-dyssynergia might therefore arise from a discrepancy in inhibitory/excitatory interneuron activity in the lumbosacral cord as well as input changes which develop over time after injury. The processes point to spinal plastic changes leading to malfunction of the important physiological pathway of lower urinary tract control.
A neural circuit for excessive feeding driven by environmental context in mice
Mohammad, H;Senol, E;Graf, M;Lee, CY;Li, Q;Liu, Q;Yeo, XY;Wang, M;Laskaratos, A;Xu, F;Luo, SX;Jung, S;Augustine, GJ;Fu, Y;
PMID: 34168339 | DOI: 10.1038/s41593-021-00875-9
Despite notable genetic influences, obesity mainly results from the overconsumption of food, which arises from the interplay of physiological, cognitive and environmental factors. In patients with obesity, eating is determined more by external cues than by internal physiological needs. However, how environmental context drives non-homeostatic feeding is elusive. Here, we identify a population of somatostatin (TNSST) neurons in the mouse hypothalamic tuberal nucleus that are preferentially activated by palatable food. Activation of TNSST neurons enabled a context to drive non-homeostatic feeding in sated mice and required inputs from the subiculum. Pairing a context with palatable food greatly potentiated synaptic transmission between the subiculum and TNSST neurons and drove non-homeostatic feeding that could be selectively suppressed by inhibiting TNSST neurons or the subiculum but not other major orexigenic neurons. These results reveal how palatable food, through a specific hypothalamic circuit, empowers environmental context to drive non-homeostatic feeding.
Buhidma, Y;Hobbs, C;Malcangio, M;Duty, S;
PMID: 37100804 | DOI: 10.1038/s41531-023-00510-3
Pain is a key non-motor feature of Parkinson's disease (PD) that significantly impacts on life quality. The mechanisms underlying chronic pain in PD are poorly understood, hence the lack of effective treatments. Using the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD, we identified reductions in dopaminergic neurons in the periaqueductal grey (PAG) and Met-enkephalin in the dorsal horn of the spinal cord that were validated in human PD tissue samples. Pharmacological activation of D1-like receptors in the PAG, identified as the DRD5+ phenotype located on glutamatergic neurons, alleviated the mechanical hypersensitivity seen in the Parkinsonian model. Downstream activity in serotonergic neurons in the Raphé magnus (RMg) was also reduced in 6-OHDA lesioned rats, as detected by diminished c-FOS positivity. Furthermore, we identified increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life. Our findings have outlined pathological pathways involved in the manifestation of pain in PD that may present targets for improved analgesia in people with PD.
Fluri F, Mützel T, Schuhmanna MK, Krstić M, Endres H, Volkmann J.
PMID: 28842194 | DOI: 10.1016/j.jneumeth.2017.08.024
Abstract
BACKGROUND:
Commercial neurostimulators for clinical use are effective in patients; however they are too large and prohibitively expensive for preclinical studies. Thus, there is an urgent need of a small inexpensive and wireless microstimulator which is fully programmable in frequency, pulse width and amplitude for rodent experiments.
NEW METHODS:
Rats were subjected to a photothrombotic stroke of the right sensorimotor cortex and a microelectrode was implanted in the right mesencephalic locomotor region. The microstimulator was connected with the head plug of the rat. Three different stimulation frequencies were applied and different stimulating amplitudes were chosen. Under these conditions, gait velocity and locomotor behavior of six rats were examined on a beam.
RESULTS:
The head-mounted microstimulator allowed freedom in all motor activities performed spontaneously by the tested rats. Increasing either the frequency or the stimulating amplitude increased gait velocity and ameliorated locomotor behavior after stroke.
COMPARISON WITH EXISTING METHODS:
Other devices for DBS in rodents must be implanted under the skin or worn in an animal jacket on the back by the tested rat. Some available systems require even a tethering of the tested animal via a cable to an external stimulation system, which limits the freedom of movement.
CONCLUSION:
Here, we present a freely programmable microstimulator including DBS-typical stimulating parameters. The lightweight device is connected by a simple plug to the head allowing full freedom of movement and exchange of batteries for long-term experiments. The design of this stimulator is suitable for sophisticated behavior tests requiring balance and skilled walking.
The Orexigenic Force of Olfactory Palatable Food Cues in Rats
Peris-Sampedro, F;Stoltenborg, I;Le May, MV;Sole-Navais, P;Adan, RAH;Dickson, SL;
PMID: 34578979 | DOI: 10.3390/nu13093101
Environmental cues recalling palatable foods motivate eating beyond metabolic need, yet the timing of this response and whether it can develop towards a less palatable but readily available food remain elusive. Increasing evidence indicates that external stimuli in the olfactory modality communicate with the major hub in the feeding neurocircuitry, namely the hypothalamic arcuate nucleus (Arc), but the neural substrates involved have been only partially uncovered. By means of a home-cage hidden palatable food paradigm, aiming to mimic ubiquitous exposure to olfactory food cues in Western societies, we investigated whether the latter could drive the overeating of plain chow in non-food-deprived male rats and explored the neural mechanisms involved, including the possible engagement of the orexigenic ghrelin system. The olfactory detection of a familiar, palatable food impacted upon meal patterns, by increasing meal frequency, to cause the persistent overconsumption of chow. In line with the orexigenic response observed, sensing the palatable food in the environment stimulated food-seeking and risk-taking behavior, which are intrinsic components of food acquisition, and caused active ghrelin release. Our results suggest that olfactory food cues recruited intermingled populations of cells embedded within the feeding circuitry within the Arc, including, notably, those containing the ghrelin receptor. These data demonstrate the leverage of ubiquitous food cues, not only for palatable food searching, but also to powerfully drive food consumption in ways that resonate with heightened hunger, for which the orexigenic ghrelin system is implicated.
Chung S, Weber F, Zhong P, Tan CL, Nguyen TN, Beier KT, Hörmann N, Chang WC, Zhang Z, Do JP, Yao S, Krashes MJ, Tasic B, Cetin A, Zeng H, Knight ZA, Luo L, Dan Y.
PMID: 28514446 | DOI: 10.1038/nature22350
In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.
Leithead, AB;Godino, A;Barbier, M;Harony-Nicolas, H;
PMID: 37245781 | DOI: 10.1016/j.biopsych.2023.05.016
The posterior intralaminar (PIL) complex of the thalamus is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed.We used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real-time during social and non-social interactions. Finally, we used inhibitory DREADDs in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation.We observed significantly more c-fos-positive cells in the PIL of mice exposed to social versus object or no stimuli. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time it took female mice to form social habituation.Together these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.
