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A decade before the rise of optogenetics, the first behavioral “circuit-test” – transgenically modulating the output of a genetically-specified brain circuit element to examine its effect on behavior – was performed. The behaviors emulated in those mice were comorbid tics and compulsions, elicited by a gene borrowed from cholera bacteria and tailored to intracellularly neuropotentiate glutamatergic somatosensory cortical and limbic output neurons of cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Two decades later, cutting-edge chemogenetic and optogenetic methods are again being devoted to further characterize the circuits thought to trigger, mediate, aggravate, or ameliorate TS & OCD symptoms. These tour de force studies support essential roles in tics and compulsions for topographically-parallel corticostriatal and amygdalar glutamatergic output neurons; their target dorsal striatal & ventral striatal (nucleus accumbens) medium spiny neurons (MSNs) of the direct striatothalamic (urge & motor activating) vs. indirect striatopallidal (urge & motor suppressing) output pathways; and their converging modulatory dopaminergic and histaminergic afferents. Going “back to the future” to circuit-map tics and compulsions will give us precision targets for future psychological, drug, medtech, and gene therapies; look for “dopamine bypasses” on your next trip in the DeLorean. [ABSTRACT FROM AUTHOR]

We recently exploited a transgenic approach to coerce macrophage anti-inflammatory M2 polarizationin vivoby lowering Receptor Interacting Protein 140 (RIP140) level in macrophages (mϕRIP140KD), which induced browning of white adipose tissue (WAT).In vitro, conditioned medium from cultured adipose tissue macrophages (ATMs) of mϕRIP140KD mice could trigger preadipocytes' differentiation into beige cells. Here we describe a cell therapy for treating high fat diet (HFD)-induced insulin resistance (IR). Injecting M2 ATMs retrieved from the WAT of mϕRIP140KD mice into HFD-fed obese adult wild-type mice effectively triggers their WAT browning, reduces their pro-inflammatory responses, and improves their insulin sensitivity. These data provide a proof-of-concept that delivering engineered anti-inflammatory macrophages can trigger white fat browning, stimulate whole-body thermogenesis, and reduce obesity-associated IR. [ABSTRACT FROM PUBLISHER]

A “Holy Grail” sought in medical treatment of obesity is to be able to biologically reprogram their adipose tissues to burn fat rather than store it. White adipose tissue (WAT) stores fuel and its expansion underlines insulin resistance (IR) whereas brown adipose tissue (BAT) burns fuel and stimulates insulin sensitivity. These two types of fats seesaw within our bodies via a regulatory mechanism that involves intricate communication between adipocytes and blood cells, particularly macrophages that migrate into adipose deposits. The coregulator, Receptor Interacting Protein 140 (RIP140), plays a key role in regulating this communication. In mice on a high-fat diet, the level of RIP140 in macrophages is dramatically elevated to activate their inflammatory M1 polarization and enhance their recruitment into WAT, facilitating IR. Conversely, lowering the level of RIP140 in macrophages not only reduces M1 macrophages but also expands alternatively polarized, anti-inflammatory M2 macrophages, triggering white adipose tissue browning, fat burning, and restoration of insulin sensitivity. This suggests a potential therapeutic strategy for reversing IR, obesity, and atherosclerotic or even cosmetic fat deposits: therapeutic browning of white adipose deposits by diminishing RIP140 levels in macrophages. [ABSTRACT FROM PUBLISHER]

Tics and compulsions in comorbid Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) are associated with chronic hyperactivity of parallel cortico/amygdalo-striato-thalamo-cortical (CSTC) loop circuits. Comorbid TS- & OCD-like behaviors have likewise been observed in D1CT-7 mice, in which an artificial neuropotentiating transgene encoding the cAMP-elevating intracellular subunit of cholera toxin (CT) is chronically expressed selectively in somatosensory cortical & amygdalar dopamine (DA) D1 receptor-expressing neurons that activate cortico/amygdalo-striatal glutamate (GLU) output. We’ve now examined in D1CT-7 mice whether the chronic GLU output from their potentiated cortical/limbic CSTC subcircuit afferents associated with TS- & OCD-like behaviors elicits desensitizing neurochemical changes in the striatum (STR). Microdialysis-capillary electrophoresis and in situ hybridization reveal that the mice’s chronic GLU-excited STR exhibits pharmacodynamic changes in three independently GLU-regulated measures of output neuron activation, co-excitation, and desensitization, signifying hyperactive striatal CSTC output and compensatory striatal glial and neuronal desensitization: 1) Striatal GABA, an output neurotransmitter induced by afferent GLU, is increased. 2) Striatal d -serine, a glial excitatory co-transmitter inhibited by afferent GLU, is decreased. 3) Striatal Period1 (Per1), which plays a non-circadian role in the STR as a GLU + DA D1- (cAMP-) dependent repressor thought to feedback-inhibit GLU + DA- triggered ultradian urges and motions, is transcriptionally abolished. These data imply that chronic cortical/limbic GLU excitation of the STR desensitizes its co-excitatory d -serine & DA inputs while freezing its GABA output in an active state to mediate chronic tics and compulsions − possibly in part by abolishing striatal Per1-dependent ultradian extinction of urges and motions. [ABSTRACT FROM AUTHOR]

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive–compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies. [ABSTRACT FROM AUTHOR]