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.
Becker, LJ;Fillinger, C;Waegaert, R;Journée, SH;Hener, P;Ayazgok, B;Humo, M;Karatas, M;Thouaye, M;Gaikwad, M;Degiorgis, L;Santin, MDN;Mondino, M;Barrot, M;Ibrahim, EC;Turecki, G;Belzeaux, R;Veinante, P;Harsan, LA;Hugel, S;Lutz, PE;Yalcin, I;
PMID: 37069164 | DOI: 10.1038/s41467-023-37878-y
While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood 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.
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.
Domi E, Uhrig S, Soverchia L, Spanagel R, Hansson AC, Barbier E, Heilig M, Ciccocioppo R, Ubaldi M.
PMID: 27810934 | DOI: 10.1523/JNEUROSCI.4127-15.2016
PPARγ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPARγ is activated by thiazolidinediones such as pioglitazone, and it is targeted to treat insulin resistance. PPARγ is densely expressed in brain areas involved in regulation of motivational and emotional processes.Here, we investigated the role of PPARγ in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPARγ by pioglitazone did not affect basal anxiety but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPARγ (PPARγNestinCre), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPARγ antagonist, elicited a marked anxiogenic response in PPARγ wild-type (Wt) but not in PPARγNestinCre KO mice. Using c-Fos immunohistochemistry we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala and the hippocampus of PPARγNestinCre KO mice compared with Wt mice. No differences were found between Wt and KO mice in hypothalamic regions responsible for hormonal response to stress, nor in blood corticosterone levels. Microinjection of pioglitazone, into the amygdala but not into the hippocampus abolished the anxiogenic response elicited by acute stress. Results also showed that in both regions PPARγ co-localizes with GABAergic cells. These findings demonstrate that neuronal PPARγ is involved the regulation of the stress response, and that the amygdala is a key substrate for the anxiolytic effect of PPARγ.
SIGNIFICANCE STATEMENT:
PPARγ is a classical target for antidiabetic therapies with thiazolidinedione compounds. PPARγ agonists, such as rosiglitazone and pioglitazone, are in clinical use for the treatment of insulin resistance. PPARγ has recently attracted attention for its involvement in the regulation of CNS immune response and functions. Here, we demonstrate that neuronal PPARγ activation prevented the negative emotional effects of stress and exerted anxiolytic actions without influencing HPA axis function. Conversely, pharmacological blockade or genetic deletion of PPARγ enhanced anxiogenic responses and increased vulnerability to stress. These effects appear to be controlled by PPARγ neuronal-mediated mechanisms in the amygdala.
