# Feedforward Activation of AgRP Neurons and Hunger

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $486,196

## Abstract

AgRP neurons play a vital role in causing hunger – the desire to find and consume food. Hence, it is important
to understand how the activity of AgRP neurons is controlled. The conventional view is that feedback signals,
which track changes in energy balance, are the primary regulators of AgRP neurons. For example, the fasting-
induced increase in AgRP neuron activity is thought to be caused by falls in leptin and perhaps insulin, and an
increase in ghrelin. Conversely, recent studies using real-time in vivo monitoring of neural activity have
unexpectedly uncovered novel forms of regulation that are clearly unrelated to feedback from energy stores.
For example, detection of sensory cues related to food, and ingestion of food, both rapidly decrease AgRP
neuron activity – well before energy stores are affected. While these examples clearly document the existence
of rapid, “feedforward” inhibition of AgRP neurons, to date there have been no examples of the converse – i.e.
rapid, feedforward activation of AgRP neurons. By performing long-term in vivo recordings of AgRP neuron
activity, we have recently discovered that denial of access to food rapidly, within 30-60 minutes, activates
AgRP neurons. Importantly, this rapid activation is to a high level that does not increase further as fasting
progresses. This relatively rapid, “square wave” pattern of activation strongly indicates that it must be caused
by novel mechanisms which, importantly, are unrelated to changes in feedback signals. This discovery, which
could lead to a revision in models of AgRP neuron regulation, indicates that fasting-related activation, like
feeding-related inhibition, utilizes feedforward mechanisms. Given that AgRP neuron activity is vital for
appetite, and given that feedforward activation is not part of present models of AgRP neuron regulation, we
believe that uncovering the neural basis for this, and establishing its function, as we recently did for sensory
food cue inhibition of AgRP neurons, will provide important, previously unknown insights into the biology of
hunger. In preliminary studies, we have identified the source of this rapid feedforward activation. Remarkably,
the excitatory circuit carrying this activation to AgRP neurons shows a large degree of activity-dependent
synaptogenesis plasticity – which we believe functions to amplify and sustain feedforward activation of AgRP
neurons. Thus, the overall goal of this grant is to discover the basis for and understand the purpose of rapid,
feedforward activation of AgRP neurons. In Aim 1 we will use our single neuron transcriptomic dataset and
marker gene recombinase driver mice to establish the neural afferent basis for this regulation. In Aim 2 we will
determine the behavioral scenarios that trigger feedforward activation – we hypothesize a key role for
awareness that food is unavailable. In Aim 3 we will establish its function – this will be done by blocking the
responsible afferents and then examining consequenc...

## Key facts

- **NIH application ID:** 10898808
- **Project number:** 5R01DK134427-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** BRADFORD B LOWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,196
- **Award type:** 5
- **Project period:** 2023-08-04 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898808

## Citation

> US National Institutes of Health, RePORTER application 10898808, Feedforward Activation of AgRP Neurons and Hunger (5R01DK134427-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898808. Licensed CC0.

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