Link to paper
Summary
- Distinct circuits for short and long timescale control
- Sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, controlling feedback behavior on both short (PRLH) and long (GCG) timescales
- PRLH neurons respond to oral cues and control short-term feeding dynamics
- PRLH neurons in the caudal nucleus of the solitary tract (cNTS) exhibit sustained activation by visceral feedback during stomach nutrient infusion
- During oral consumption, PRLH neurons shift to a phasic activity pattern linked to the taste of food
- Optogenetic manipulations show that PRLH neurons regulate the duration of seconds-timescale feeding bursts
- GCG neurons respond to GI feedback for long-term satiety
- GCG neurons in the cNTS are activated by mechanical feedback from the gut and track the cumulative amount of food consumed.
- GCG neurons promote long-lasting satiety that persists for tens of minutes, influencing the initiation of subsequent feeding bouts.
The Paper
Background
what is the gap in knowledge this research is trying to address?
- To address the gap in our understanding of how sensory signals generated during a meal are encoded in caudal brainstem circuits (caudal nucleus of the solitary tract, aka the cNTS, specifically), in awake animals, and how these circuits transform sensory signals into dynamic control of feeding behavior
- Prior research has primarily relied on recordings in anesthetized animals, which lacks most of the sensory and motor feedback generated during natural ingestion
Hypothesis
- Distinct cell types, specifically prolactin-releasing hormone (PRLH) and glucagon-like peptide 1 (GCG) neurons in the cNTS, play key roles in encoding and processing sensory signals related to feeding
Experiments
- Investigation of PRLH Neurons:
- Recorded PRLH neuron activity in awake mice during ingestion using fiber photometry
- Examined responses to intragastric (IG) nutrient infusions and oral consumption of various substances, including glucose, fat, and sucralose
- Conducted experiments to test the necessity of gastrointestinal (GI) signals during oral ingestion, including the use of CCK injection and CCK receptor antagonists
- Tracking Ingestion Dynamics of PRLH Neurons:
- Monitored PRLH neuron activity during self-paced feeding in fasted mice
- Analyzed the correlation between PRLH neuron activity and oral contact with food, taste, and macronutrient intake
- Distinguishing Responses to Taste and Nutrient Content:
- Investigated the role of taste in PRLH neuron activation by crossing Prlhcre mice with taste-blind Trpm5 knockout mice
- Compared responses to sweet taste (sucralose) and non-nutritive oral infusions to distinguish taste-related activation from nutrient-related activation
- Single-Cell Imaging of PRLH Neurons:
- Conducted stable single-cell recordings of PRLH neurons in awake, head-fixed mice during consumption of liquid diets
- Analyzed responses to different tastants, including glucose, intralipid , and sucralose, to characterize the dynamics of PRLH neuron activity
- Manipulation of PRLH Neuron Activity:
- Optogenetically stimulated PRLH neurons during licking to understand their role in controlling feeding bursts
- Used closed-loop optogenetics to selectively stimulate or silence PRLH neurons during licking and assess their impact on feeding behavior
- Investigation of GCG Neurons:
- Recorded GCG neuron activity using fiber photometry in awake mice during consumption of various substances, including Ensure, glucose, Intralipid, chow, and high-fat diet
- Examined the correlation between GCG neuron activation and oral intake, GI stretch, and cumulative food intake
- Assessment of GCG Neuron Effects on Feeding:
- Optogenetically stimulated GCG neurons continuously to inhibit the consumption of solid and liquid food
- Employed closed-loop optogenetics to selectively stimulate GCG neurons during licking and assess their impact on feeding bouts
- Pre-Stimulation Protocol for Long-Lasting Satiety:
- Pre-stimulated GCG neurons optogenetically in the absence of food to mimic post-prandial activation
- Investigated the long-lasting effects of GCG neuron pre-stimulation on subsequent feeding behavior
Observations
- PRLH Neurons:
- Activated during orosensory stimulation and correlated with macronutrient intake
- Responsive to both taste and nutrient content
- Showed bursts of activity during licking bouts.
- GCG Neurons:
- Activated during oral intake and correlated with cumulative food intake
- Responded to GI stretch signals
- Stimulation of GCG neurons led to inhibition of feeding
- Taste and Nutrient Discrimination:
- PRLH neurons responded to both taste and nutrient-related signals
- GCG neurons were more closely associated with nutrient-related signals
- Distinct Roles:
- PRLH neurons involved in short-term orosensory control
- GCG neurons implicated in long-term post-ingestive feedback regulation
- Optogenetic Stimulation Effects:
- Optogenetic stimulation of PRLH neurons influenced feeding bursts
- Continuous optogenetic stimulation of GCG neurons inhibited food consumption
- Pre-Stimulation Effects on Satiety
- Pre-stimulation of GCG neurons led to long-lasting inhibition of subsequent feeding.
Conclusions
- Dual Control Mechanism:
- PRLH neurons involved in immediate orosensory control
- GCG neurons contribute to longer-term post-ingestive feedback regulation
- Taste and Nutrient Integration:
- PRLH neurons integrate both taste and nutrient signals
- GCG neurons respond more strongly to nutrient-related signals
- GCG Neurons in Satiety Induction:
- Pre-stimulation of GCG neurons induces lasting satiety effects
- Potential Therapeutic Targets:
- PRLH and GCG neurons represent potential targets for controlling feeding behavior and addressing metabolic disorders
- Complementary Roles:
- PRLH and GCG neurons act synergistically to regulate feeding through distinct mechanisms
- Understanding their interplay provides insights into the complexity of feeding control