Brain Control of Physiology and Behavior

We seek to identify the neural mechanisms responsible for brain control of homeostatic drives (e.g. hunger), the autonomic nervous system, neuroendocrine systems, hormones and metabolism. 

To achieve this, we interrogate the input/output connectivity, regulation and function of genetically-identified neurons.  This is done by combining genetically engineered mice that express, in a neuron-specific fashion, DNA recombinases (Cre, Flp, etc.) with AAVs or mice that express, in a recombinase-dependent fashion, a panel of “neuroscience tools”.  With this approach, for any given neuron we can:  a) manipulate its firing rate to determine its role in regulating behavior and physiology, b) measure its activity in vivo to establish how that neuron responds to discrete sensory, behavioral and physiologic stimuli, and c) map its synaptic connectivity with upstream and downstream and neurons to uncover the underlying neural “wiring diagrams”.  This information allows us to construct mechanistic models of how the brain controls physiology and behavior.

Techniques utilized include, electrophysiology, optogenetics, chemogenetics, rabies monosynaptic mapping, ChR2-assisted circuit mapping, in vivo assessments of neuronal activity, and single neuron transcriptomics (the latter to discover neuron subtypes, along with their genetic markers, that constitute key nodes in the brain).

Recent discoveries and accomplishments include: 

1) the arcuate  PVH  LPBN neural circuitry responsible for regulating hunger / satiety.

2) upstream afferent neurons that connect to and regulate AgRP hunger neuron activity.

3) the basis for and function of sensory food cue regulation of AgRP hunger neurons.

4) highly selective “labeled lines” used by vagal motor neurons for brain-to-gut communication.

5) generation of > 50 lines of mice used widely ( > 1,300 publications; Jax MGI database).   

Recent reviews: 

Andermann ML, Lowell BB. Toward a wiring diagram understanding of appetite control.  Neuron  95:  757-78, 2017.

Lowell BB, New neuroscience of homeostasis and drives for food, water, and salt. N Engl J Med 380: 459-471, 2019.

Lowell BB, Swanson LW, Horn JP, Chapter 41 – The Hypothalamus:  Autonomic, Hormonal and Behavioral Control of Survival – in 6th Edition of Principles of Neural Science, Editors:  Kandel ER et al., McGraw Hill, 2021.

Recent primary references:

  1. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD, Lowell BB. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507: 238-42, 2014.  PMCID:  PMC3955843

  2. Shah BP, Vong L, Olson DP, Koda S, Krashes MJ, Ye C, Yang Z, Fuller PM, Elmquist JK*, Lowell BB*. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A 111: 13193-8, 2014.  PMCID:  PMC4246954. *Co-senior authors.

  3. Garfield AS*, Li C, Madara JC, Shah BP, Webber E, Steger JS, Campbell JN, Gavrilova O, Lee CE, Olson DP, Elmquist JK, Tannous BA, Krashes MJ*, Lowell BB*. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci 18: 863-71, 2015.  PMCID:  PMC4446192. *Co-senior authors.

  4. Garfield AS*, Shah BP, Burgess CR, Li MM, Li C, Steger JS, Madara JC, Campbell JN, Kroeger D, Scammell TE, Tannous BA, Myers MG, Jr., Andermann ML, Krashes MJ*, Lowell BB*. Dynamic GABAergic afferent modulation of AgRP neurons. Nat Neurosci 19: 1628-1635, 2016.   PMCID:  PMC5382799. *Co-senior authors.

  5. Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, Goldman M, Verstegen AM, Resch JM, McCarroll SA, Rosen ED*, Lowell BB*, Tsai LT*. A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20: 484-496, 2017. PMCID:  PMC5323293. *Co-senior authors.

  6. Fenselau H, Campbell JN, Verstegen AM, Madara JC, Xu J, Shah BP, Resch JM, Yang Z, Mandelblat-Cerf Y, Livneh Y, Lowell BB. A rapidly acting glutamatergic ARC  PVH satiety circuit postsynaptically regulated by alpha-MSH. Nat Neurosci 20: 42-51, 2017.  PMCID:  PMC5191921.

  7. Livneh Y, Ramesh RN, Burgess CR, Levandowski KM, Madara JC, Fenselau H, Goldey GJ, Diaz VE, Jikomes N, Resch JM, Lowell BB*, Andermann ML*. Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546: 611-616, 2017.  PMCID:  PMC5577930.

  8. Resch JM, Fenselau H, Madara JC, Wu C, Campbell JN, Lyubetskaya A, Dawes BA, Tsai LT, Li MM, Livneh Y, Ke Q, Kang PM, Fejes-Toth G, Naray-Fejes-Toth A, Geerling JC*, Lowell BB*. Aldosterone-sensing neurons in the NTS exhibit state-dependent pacemaker activity and drive sodium appetite via synergy with angiotensin II signaling. Neuron 96, 190–206, 2017.   PMCID:  PMC5637454. *Co-senior authors.

  9. Li MM, Madara JC, Steger JS, Krashes MJ, Balthasar N, Campbell JN, Resch JM, Conley NJ, Garfield AS*, Lowell BB*. The paraventricular hypothalamus regulates satiety and prevents obesity via two genetically distinct circuits. Neuron, 102: 653-667,  2019.   PMCID:  PMC6508999. *Co-senior authors.

  10. Livneh Y, Sugden AU, Madara JC, Essner RA, Flores VI, Sugden LA, Resch JM, Lowell BB*, Andermann ML*. Estimation of current and future physiological states in insular cortex. Neuron 105:  1094-1111, 2020. PMCID:  PMC7083695.

  11. Tao J*, Campbell JN*,**, Tsai LT, Wu C, Liberles SD, Lowell BB**. Highly selective brain-to-gut communication via genetically-defined vagus neurons.  Neuron, doi:  10.1016/j.neuron.2021.05.004. Online ahead of print.  *joint first authors.  **co-senior authors.

     

  12. Berrios J, Li C, Madara JC, Garfield AS, Steger JS, Krashes MJ, Lowell BB. Food cue inhibition of AgRP hunger neurons guides learning.  Nature – IN PRESS.