Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone

Abstract

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-specific manner

“…Bilateral stereotaxic injections where then given for the AAV2-DIO-rMCHp-hM3D(Gq)-mCherry (Cre-dependent MCH DREADDs; titer 1.1x10 13 GC/ml) at the following coordinates: injection (1) −2.6 mm AP, ±1.8 mm ML, −8.0 mm DV; (2) −2.6 mm AP, ±1.0 mm ML, −8.0 mm DV; (3) −2.9 mm AP, ±1.1 mm ML, −8.8 mm DV; (4) −2.9 mm AP, ±1.6 mm ML, −8.8 mm DV (from the skull surface at bregma). Our previous publications show that this AAV is selective to MCH neurons (IHC verification), and that DREADDs are functional in MCH neurons (behavioral and electrophysiological verification) Noble et al, 2019). Present results are comparable to our previous application of this method in the ACBsh, which yielded ~10% of total MCH neurons transfected with DREADDS, and ~100% of cells transfected with DREADDs that were also MCH+ neurons .…”

“…ACB MCH1R-expressing neurons and glial cells are not exclusively engaged by MCH signaling under physiological conditions, but also by various neurochemicals that are coreleased by LHA/ZI MCH neurons. Here we utilized our recently validated dual-viral chemogenetic approach Noble et al, 2019) to reversibly and selectively activate MCH neurons that project to the ACBsh. Similar to ACBsh-targeted MCH1R pharmacology, results reveal that ACBsh-projecting MCH neuron activation increases intake of both chow and palatable sucrose in male rats, thus revealing a novel role for this population of neurons in feeding behavior.…”

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network

“…For instance, lesions to [32] or manipulation of the activity of the subthalamic nucleus using deep brain stimulation [33] results in an increase of premature responding in this task. The hypothalamus was also shown to be implicated in impulsive actions via its connections with the hippocampus [34] as well as with the mesolimbic dopaminergic system [35]. The mammillary bodies were shown to be implicated in the anticipation of reward in humans [36].…”

Control of fear extinction by hypothalamic melanin-concentrating hormone–expressing neurons

“…These findings are unexpected and cannot be inferred from existing studies of MNs. While it has been proposed that MNs can modulate a number of learned and innate behaviors as well as synaptic plasticity via their brain-wide projections and/or volume transmission of MCH, no previously reported evidence suggested their involvement in extinction of cued fear responses ( 20 – 25 , 31 , 35 – 39 ).…”