# Presentation: 353461

## Corticostriatal-hypothalamiccircuitry and motivation for food: integration of reward, cognition and energy

- Ann E. Kelley, Ph.D.
- Department of Psychiatry
- Neuroscience Training Program
- University of Wisconsin-Madison

## Obesity: An emerging major public health problem

- • Half a million deaths per year attributed to obesity
- • Half a million deaths attributed to addiction-related disorders
- • “Disorders of appetitive motivation” are by far the largest cause of morbidity and mortality in this country

## Biological, evolutionary and social factorsunderlying the obesity epidemic

- Body and brain systems to control food intake are evolutionarily ancient systems, developed hundreds of millions of years ago
- Critical for survival of individual and species
- Most awake time in human societies spent hunting, gathering, agricultural labor, preparing food (very high energy expenditure)
- Powerful biologically-based drives in the brain, hard-wired through evolution, have not “caught up” with cultural changes
- These drives are associated with strong affective states (needs, cravings, desires) triggered by palatable food stimuli
- Calorie-dense food provides powerful pleasure signals

## Recent research has characterized hypothalamic peptide-coded metabolic sensing pathways 

- These hypothalamic peptide sensing systems are extremely important in triggering hunger and food search, satiety and long-term fat store signals to the brain
- However, other brain circuits appear to be important in mediating the motivational, cognitive and emotional components of eating behavior

- Nucleus accumbens
- (ventral striatum)

## Pathways that link the nucleus accumbens with circuits involved in the control of taste perception, energy balance, food intake, and cognitive/emotional processes

- Blue output pathways: opioid/palatability
- Red output pathways: GABA/energy
- deficit/motor patterns/autonomic
- 	*Dopamine modulates
- 	many regions

***Hedonic/emotion***

## Underlying hypotheses:

- Amino acid-coded (GABA, glutamate) neurons within the ventral striatum (AcbSh subregion) link forebrain circuitry to hypothalamic energy-balance sensors and brainstem motor pattern generators (“on-off switch”; “sensory sentinel”)
- Opioid peptide-coded neurons in the ventral striatum encode the affective or hedonic response to food and engage  frontotemporal cortical systems (“this tastes/feels great”)
- Dopamine and glutamate signals within ventral striatum and associated circuitry enable systems-wide plasticity for searching for, anticipating, and learning about food and resources in the environment (“remember where and how”)
- Addictive drugs act on and alter these neural systems encoding appetitive motivation

## Slide 8

## Intake of either fat or carbohydrate is increased when diets given separately

- Opioids selectively enhance fat intake
- when rats have a choice of diets

- Zhang et al. 2000

- Mansour et al.

## Intra-Accumbens administration of the μ-opioid agonist

**+**
- Intra-BLA Saline

- Intra-Accumbens DAMGO
**+**
- Intra-BLA-Muscimol (20ng/0.25μl)

- DAMGO produces a robust feeding effect

## Inactivation of basolateral amygdala prevents the opioid-induced fat intake, while inactivation of central amygdala abolishes fat intake

- Intake of fat or liquid Ensure increases Fos
- expression in central amygdala

- (M. Will et al
- Submitted 2004)

## Accumbens shell/muscimol-induced (and opioid-induced) feeding is dependent on lateral hypothalamic activation

- (Maldonado-Irizarry et al. JN 1995, Stratford & Kelley, JN 1999)

## Comparison of GABA/Glu and mu opioid-codedfood motivation systems within accumbens:

- GABA/Glu
- Restricted to medial shell
- Not macronutrient- or taste-selective
- Increased sucrose intake; not saccharin or salt
- Fos profile: PVN, perifornical LH,
- supramammillary, arcuate
-  VTA, NTS
- Blocked by central amyg. inactivation;
- not by basolateral
- No increase in breakpoint/progressive ratio
- Interacts with brainstem motor pattern generators
-      and sensitive to energy deficit

- Mu Opioid
- Diffuse throughout ventral  (and
- maybe dorsal/patch>? striatum).
- Macronutrient-selective (fat)
- Increased sucrose, saccharin & salt
- Fos profile: Dorsomedial
- hypothal., LH, supramammillary,
- VTA, NTS
- Blocked by central amyg. Inactivation,
- also by basolateral
- Increased breakpoint/progressive ratio
- Interacts with forebrain voluntary motor
-      circuits and is sensitive to palatability

- GABA-coded feeding elicited from Acb shell activates
- both the LH and arcuate nucleus

*Baldo et al., EJN 2004*

## Restricted daily intake of highly palatable food causes down regulation of striatal preproenkephalin gene expression as does chronic treatment with morphine

- (Georges et al EJN 1999)

- (Kelley et al. EJN 2003)

- PPE - placebo

- PPE - Chronic morphine

## }

- Food restricted group
- (n = 12)

- Ad libitum-fed group
- (n = 12)

- Evening of last day:

- Food (n = 6)
- No food (n = 6)

- Food (n = 6)
- No food (n = 6)

- How does enkephalin mRNA expression change with
- different motivational conditions?

- Northern
- Blot
- analysis

## *

- Hypothalamus Neuropeptide Y mRNA

- How does ventral striatal enkephalin mRNA expression change with different motivational conditions?

*****

**#**

*****

**#**

*(Will, Van der Heyden, Kelley, unpublished)*

**(3mm diameter punch dissections - Northern blot analysis)**

- Accumbens
- Preproenkephalin mRNA

**Notes:**
2wk FD effects on Acb PPE and Hypo NPY

## Gene expression in relation to food intake in

**Food**

**No food**

**Food**

**No food**

- rats with *ad libitum access* to food

- Preproenkephalin mRNA

- Neuropeptide Y mRNA

## Gene expression in relation to food intake in

**No food**

**Food**

**No food**

- rats with *restricted access* to food

- Preproenkephalin mRNA

- Neuropeptide Y mRNA

## Before instrumental learning 

- Before instrumental learning

- After instrumental learning

- What about dopamine?
- Coincident activation of dopamine D1 receptors and glutamate NMDA
- receptors, leading to intracellular second messenger activity and
- gene transcription, *in the nucleus accumbens and its associated networks*, is necessary for “action-outcome” (instrumental/operant) learning

- Kelley et al., PNAS 1997
- Smith-Roe & Kelley , JN 2000
- Baldwin et al., Behav Neurosci 2000

- Baldwin et al. JN, 2002
- Baldwin et al. Neurobiol Learn Mem 2002
- Hernandez et al, Nat Neurosci 2002

## Plasticity in corticolimbic striatal networks is critical for normal (“natural”) reward learning, but also contributes to drug-associated neuroadaptations within these networks

- Learning
- & memory

- Drug/food
- -induced

- Cue-induced

- Associative processing

- UCR
- (positive affect)

- UCS
- (drug, food)

- CS
- (environmental
- cues; “context”)

- CR
- (Craving; drug, food-related
- thoughts; drug, food-seeking)

- Gene
- expression profile in
- corticolimbic regions

## Saline-paired context

- Morphine-paired
- context

- 100 x

- Control context

- 100x magnification

**PL**

**PL**

**C**

- POA

- Prefrontal cortex is activated by both natural and
- drug-associated conditioned cues

- Control context

- Chocolate-paired
- context

- (From Schroeder et al.,
- Neuroscience 2001)

## Cues associated with nicotine (or morphine) alter brain expression of Arc mRNA

- • All rats have had
- the same experience with
- nicotine. However, “paired
- rats have been placed in
- drug-associated environment,
- while “unpaired” rats were
- placed in the saline-associated
- environment

- • Arc: a dendritically targeted
- mRNA; protein thought
- to play a role in synaptic
- Plasticity and tagging.
- Expression is dependent on
- NMDA receptor activation

- Blue output pathways: opioid/palatability
- Red output pathways: GABA/energy
- deficit/motor patterns/autonomic
- 	*Dopamine modulates
- 	many regions

## Thanks to lab members past and 

*Ana Maria Basso*
*Chad Swanson*
*Thomas Stratford*
*Min Zhang*
*Vaishali Bakshi*
*Teresa Steininger*
*Stephanie Smith-Roe*
*Matthew Holahan*
*Brock Schroeder*
*Anne Baldwin*

- Matt Andrzejewski 	Craig Schiltz
- Brian Baldo  	Ken Sadeghian
- Erin Hanlon	Rob Spencer
- Pepe Hernandez 	Matt Will
- Wayne Pratt	Willie Van der Heyden
- Teri Schochet
- 			Suzanne Haber (U.Rochester)
- 			Charles Landry, Pat Roseboom

*Thanks to lab members past and *
*present!*

## Intracranial stimulation reward provides clues about brain reinforcement mechanisms

## http://www.theonion.com/onion3531/gene_chips.html

-       According to the Cornell team, series CHP-48/OZ-379 is a set of "alleles," or collections of genetic material, that cause chip-eaters to develop a markedly larger number of chip-responsive nerve endings in their cerebral material.
-       "People with this gene have up to four times the amount of fritoceptors normally found in a human," Alvaro said. "This increases their pleasure response to snaxamine-2, the human body's principal chip-eating hormone, which is released in response to giant handfuls of chips being shoveled into the mouth. This tends to promote entire-goddamn-bag-eating behavior in those individuals who possess the series."

-     ITHACA, NY—In an announcement with major implications for future generations of big fat hogs, Cornell University geneticists announced Monday that they have isolated the specific DNA series that makes an individual susceptible to eating a whole goddamn bag of chips.

## Neuropeptide Y mRNA expression 

**Food Last Day?**

**Yes**

**Yes**

**No**

**No**

**Food Last Day?**

_**Neuropeptide Y**_** mRNA expression**

**Ad Libitum Food**

**Food Restricted**

## The “central command” for eating appears to be the arcuate

- The “central command” for eating appears to be the arcuate
- nucleus, at the base of the hypothalamus, where cells are
- exquisitely sensitive to the body environment.  The arcuate nucleus
- has connections to the lateral hypothalamus, a region
- which has massive connections with emotional and cognitive brain
- regions, as well as links to downstream visceral and autonomic motor
- areas

*From  Science, 2003*

**Notes:**
Marx, J. (2003) Cellular warriors at the battle of the bulge. Science 299:846-849.

## Neuropeptide Y mRNA expression 

**Food Last Day?**

**Yes**

**Yes**

**No**

**No**

**Food Last Day?**

_**Neuropeptide Y**_** mRNA expression**

**Ad Libitum Food**

**Food Restricted**

## Ad Libitum Food

**Food Last Day?**

**Yes**

**Yes**

**No**

**No**

**Food Last Day?**

**Ad Libitum Food**

_**Preproenkephalin**_** mRNA expression**
**(*****in situ***** hybridization)**

**Food Restricted**