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A novel approach to map induced activation of neuronal networks using chemogenetics and functional neuroimaging in rats: A proof-of-concept study on the mesocorticolimbic system

Theresia J.M. Roelofs, Jeroen P.H. Verharen, Geralda A.F. van Tilborg ,Linde Boekhoudt ,Annette van der Toorn, Johannes W. de Jong ,Mieneke C.M. Luijendijk ,Willem M. Otte,Roger A.H. Adan  

Neuroimage 156 (2017) 109-118

Linking neural circuit activation at whole-brain level to neuronal activity at cellular level remains one of the major challenges in neuroscience research. We set up a novel functional neuroimaging approach to map global effects of locally induced activation of specific midbrain projection neurons using chemogenetics (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-technology) combined with pharmacological magnetic resonance imaging (phMRI) in the rat mesocorticolimbic system. Chemogenetic activation of DREADD-targeted mesolimbic or mesocortical pathways, i.e. projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) or medial prefrontal cortex (mPFC), respectively, induced significant blood oxygenation level-dependent (BOLD) responses in areas with DREADD expression, but also in remote defined neural circuitry without DREADD expression. The time-course of brain activation corresponded with the behavioral output measure, i.e. locomotor (hyper)activity, in the mesolimbic pathway-targeted group. Chemogenetic activation specifically increased neuronal activity, whereas functional connectivity assessed with resting state functional MRI (rs-fMRI) remained stable. Positive and negative BOLD responses distinctively reflected simultaneous ventral pallidum activation and substantia nigra pars reticulata deactivation, respectively, demonstrating the concept of mesocorticolimbic network activity with concurrent activation of the direct and indirect pathways following stimulation of specific midbrain projection neurons. The presented methodology provides straightforward and widely applicable opportunities to elucidate relationships between local neuronal activity and global network activity in a controllable manner, which will increase our understanding of the functioning and dysfunctioning of large-scale neuronal networks in health and disease.


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A tale of gastric layering and sieving: Gastric emptying of a liquid meal with water blended in or consumed separately

Guido Camps, Monica Marsa, Cees de Graaf, Paul A.M. Smeets

Physiology & Behaviour (in press)

The process of gastric emptying determines how fast gastric content is delivered to the small intestine. It has been shown that solids empty slower than liquids and that a blended soup empties slower than the same soup as broth and chunks, due to the liquid fraction emptying more quickly. This process of ‘gastric sieving’ has not been investigated for liquid foods.
To determine whether gastric sieving of water can also occur for liquid foods. Two groups of men participated in a parallel design (n =15, age 22.6 ± 2.4 y, BMI 22.6 ± 1.8 kg/ m2, and n =19, age 22.2 ± 2.5 y, BMI 21.8 ± 1.5 kg/m2) and consumed an isocaloric shake (2093 kJ, CARBOHYDRATES: 71 g, FAT: 18 g, PROTEIN: 34 g), either in a 500-mL version (MIXED) or as a 150-mL shake followed by 350 mL water (SEPARATE). Participants provided appetite ratings and were scanned using MRI to determine gastric emptying rate and volume at three time-points within 35 min post ingestion.
Gastric emptying - the percentage emptied in 35 min was significantly smaller for MIXED (29 ± 19%) than for SEPARATE (57 ± 11%, p < 0.001).  In the present study we show that gastric sieving can occur for liquid foods; water is able to drain
from the stomach while a layer of nutrient rich liquid is retained. In indirect gastric emptying measurements, the
behavior of labelling agents may be affected by the layering and confound emptying measurements

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Modulation of attentional networks by food-related disinhibition

Maike A. Hege , Krunoslav T. Stingl, Ralf Veit, and Hubert Preissl

Physiology and Behaviour 2017 (in press)

The risk of weight gain is especially related to disinhibition, which indicates the responsiveness to external food stimuli with associated disruptions in eating control.We adapted a food-related version of the attention network task and used functional magnetic resonance imaging to study the effects of disinhibition on attentional networks in 19 normal-weight participants. High disinhibition scores were associated with a rapid reorienting response to food pictures after invalid cueing and with an enhanced alerting effect of awarning cue signalizing the upcoming appearance of a food picture. Imaging data revealed activation of a right-lateralized ventral attention network during reorienting. The faster the reorienting and the higher the disinhibition score, the less activation of this network was observed. The alerting contrast showed activation in visual, temporo-parietal and anterior sites. These modulations of attentional networks by food-related disinhibition might be related to an attentional bias to energy dense and palatable food and increased intake of food in disinhibited individuals.

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Acute ghrelin changes food preference from high fat diet to chow during binge-like eating in rodents

Tina Bake, Kim T Hellgren and Suzanne L Dickson

Journal of Neuroendocrinology 2017, Vol 29 1-12

Ghrelin, an orexigenic hormone released from the empty stomach, provides a gut–brain signal that promotes many appetitive behaviours, including anticipatory and goal-directed behaviours for palatable treats high in sugar and/or fat. In the present study, we aimed to determine whether ghrelin is able to influence and/or may even have a role in binge-like eating behaviour in rodents. Accordingly, we used a palatable scheduled feeding (PSF) paradigm in which ad lib. chow-fed rodents are trained to ‘binge’ on a high-fat diet (HFD) offered each day for a limited period of 2 hours. After 2 weeks of habituation to this paradigm, on the test day and immediately prior to the 2-hour PSF,rats were administered ghrelin or vehicle solution by the i.c.v. route. Remarkably and unexpectedly, during the palatable scheduled feed, when rats normally only binge on the HFD, those injected with i.c.v. ghrelin started to eat more chow and chow intake remained above baseline for the rest of the 24-hour day. We identify the ventral tegmental
area (VTA) (a key brain area involved in food reward) as a substrate involved because these effects could be reproduced, in part, by intra-VTA delivery of ghrelin.
Fasting, which increases endogenous ghrelin, immediately prior to a palatable schedule feed also increased chow intake during/after the schedule feed but, in contrast to ghrelin injection, did not reduce HFD intake. Chronic continuous central ghrelin infusion over several weeks enhanced binge-like behaviour in palatable schedule fed rats.
Over a 4-week period, GHS‐R1A‐KO mice were able to adapt and maintain large meals of HFD in a manner similar to wild-type mice, suggesting that ghrelin signalling may not have a critical role in the acquisition or maintenance in this kind of feeding behaviour. In conclusion, ghrelin appears to act as a modulating factor for binge‐like eating behaviour
by shifting food preference towards a more nutritious choice (from HFD to chow), with these effects being somewhat divergent from fasting.

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Beyond carrots and sticks: Europeans support health nudges

Lucia A. Reisch , Cass R. Sunstein  and Wencke Gwozdz

Food Policy 69 (2017) 1-10

All over the world, nations are using ‘‘health nudges” to promote healthier food choices and to reduce the health care costs of obesity and non-communicable diseases. In some circles, the relevant reforms are controversial. On the basis of nationally representative online surveys, we examine whether Europeans favour such nudges. The simplest answer is that majorities in six European nations (Denmark, France, Germany, Hungary, Italy, and the UK) do so. We find majority approval for a series of nudges, including educational messages in movie theaters, calorie and warning labels, store placement promoting healthier food, sweet-free supermarket cashiers and meat-free days in cafeterias. At the same time, we find somewhat lower approval rates in Hungary and Denmark. An implication for policymakers is that citizens are
highly likely to support health nudges. An implication for further research is the importance of identifying the reasons for cross-national differences, where they exist.

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Sensory specific satiety: More than ‘just’ habituation?

Laura L. Wilkinson,  Jeffrey M. Brunstrom

Appetite 103 (2016) 221-228

Sensory specific satiety (SSS) describes the decline in pleasantness associated with a food as it is eaten relative to a food that has not been eaten (the ‘eaten’ and ‘uneaten’ foods, respectively). The prevailing view is that SSS is governed by habituation. Nevertheless, the extent to which SSS results solely from this ‘low-level’ process remains unclear. Three experiments were conducted to explore the hypothesis that ‘top-down’ cognitive activity affects the expression of SSS; specifically, we manipulated participants' expectations about whether or not they would have access to alternative test foods (uneaten foods) after consuming a test meal (eaten food). This manipulation was motivated by ‘Commodity Theory,’ which describes the relative increase in value of a commodity when it becomes unavailable. We tested the hypothesis that a decline in the pleasantness and desire to eat the eaten food is exaggerated when uneaten foods are unavailable to participants. None of our findings supported this proposition - we found no evidence that SSS is dependent on top-down processes associated with the availability of other uneaten test foods.

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Do Europeans like nudges?

Lucia A. Reisch abd Cass R. Sunstein

Judgment and Decision Making, Vol. 11, No. 4, July 2016, pp. 310–325

In recent years, many governments have shown a keen interestin “nudges” — approaches to law and policy that
maintain freedom of choice, but that steer people in certain directions (Halpern, 2015; Thaler & Sunstein, 2008).
In 2010, the United Kingdom established a Behavioural Insights Team, which now has an extensive track record
(Halpern, 2015). In 2014, the United States created a Social and Behavioral Sciences Team of its own (SBST, 2015),
and President Obama formally embraced the approach with an important Executive Order in 2015 (Obama, 2015). Both
Australia and Germany established their own behavioral science teams in 2015. Uses of behavioral science, with particular emphasis on nudges, have attracted increasing interest all over the world (Ly & Soman, 2013; Sunstein, 2016a), and perhaps especially in Europe (Whitehead et al., 2014). To date, there is little information about whether citizens of various nations actually endorse nudges, and more particularly, about the line between those that they would endorse and those that they would reject.

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Elasticity in portion selection is predicted by severity of anorexia and food type in adolescents

M. Herzog, C.R. Douglas, H.R. Kissileff , J.M. Brunstrom, K.A. Halmi

Appetite 103 (2016) 87-94

The size of portions that people select is an indicator of underlying mechanisms controlling food intake. Fears of eating excessive portions drive down the sizes of portions patients with anorexia nervosa (AN) can tolerate eating significantly below those of healthy controls (HC) (Kissileff et al., 2016). To determine whether patients with AN will also reduce the sizes of typical or ideal portions below those of controls, ANOVA was used to compare maximum tolerable, typical, and ideal portions of four foods (potatoes, rice, pizza, and M&M's) in the same group of 24 adolescent AN patients and 10 healthy adolescent controls (HC), on which only the maximal portion data were previously reported. Typical and ideal portion sizes did not differ on any food for AN, but for HC, typical portions sizes (kcals) became larger than ideal as the
energy density of the food increased, and were significant for the most energy dense food. Ideal portions of low energy dense foods were the same for AN as for in HC. There was a significant 3-way (group  food  portion type) interaction, such that HC selected larger maximum than typical portions only for pizza.We therefore proposed that individuals of certain groups, depending on the food, can be flexible in the amounts of food chosen to be eaten. We call this difference between maximumtolerable, and typical portion sizes selected “elasticity.” Elasticity was significantly smaller for AN patients compared to HC for pizza and was significantly inversely correlated with severity of illness. This index could be useful for clinical assessment of AN patients, and those with eating problems such as in obesity and bulimia nervosa and tracking their response to treatment.

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Large Portions Encourage the Selection of Palatable Rather Than Filling Foods

Jeffrey M Brunstrom, Andreas Jarvstad, Rebecca L Griggs, Christina Potter, Natalie R Evans, Ashley A Martin,

Jon CW Brooks, and Peter J Rogers

Journal of Nutriton 2016, 146: 2117-2123

Portion size is an important driver of larger meals. However, effects on food choice remain unclear. Our aim was to identify how portion size influences the effect of palatability and expected satiety on choice.

In study 1 adult participants (n = 24, 87.5% women) evaluated the palatability and expected satiety of 5 lunchtime meals and ranked them in order of preference. Separate ranks were elicited for equicaloric portions from 100 to 800 kcal (100-kcal steps). In study 2, adult participants (n = 24, 75% women) evaluated 9 meals and ranked 100–600 kcal portions in 3 contexts (scenarios), believing that 1) the next meal would be at 1900, 2) they would receive only a bite of one food, and 3) a favorite dish would be offered immediately afterwards. Regression analysis was used to
quantify predictors of choice.

In Study 1, the extent to which expected satiety and palatability predicted choice was highly dependent on
portion size (P < 0.001). With smaller portions, expected satiety was a positive predictor, playing a role equal to palatability (100-kcal portions: expected satiety, b: 0.42; palatability, b: 0.46). With larger portions, palatability was a strong predictor (600-kcal portions: b: 0.53), and expected satiety was a poor or negative predictor (600-kcal portions: b: 20.42).

In Study 2,this pattern was moderated by context (P = 0.024). Results from scenario 1 replicated Study 1. However, expected satietywas a poor predictor in both scenario 2 (expected satiety was irrelevant) and scenario 3 (satiety was guaranteed), and palatability was the primary driver of choice across all portions.

In adults, expected satiety influences food choice, but only when small equicaloric portions are compared. Larger portions not only promote the consumption of larger meals, but they encourage the adoption of food choice strategies motivated solely by palatability

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Oxytocin Neurones: Intrinsic Mechanisms Governing the Regularity of Spiking Activity

J. Maícas Royo, C. H. Brown, G. Leng and D.J.MacGregor

Journal of Neuroendocrinology, 28 10.1111 2016

Oxytocin neurones of the rat supraoptic nucleus are osmoresponsive and, with all other things being equal, they fire at a mean rate that is proportional to the plasma sodium concentration. However, individual spike times are governed by highly stochastic events, namely the random occurrences of excitatory synaptic inputs, the probability of which is increased by increasing extracellular osmotic pressure. Accordingly, interspike intervals (ISIs) are very irregular. In the present study, we show, by statistical analyses of firing patterns in oxytocin neurones, that the mean firing rate as measured in bins of a few seconds is more regular than expected from the variability of ISIs. This is consistent with an intrinsic activity-dependent negative-feedback mechanism. To test this, we compared observed neuronal firing patterns with firing patterns generated by a leaky integrate-and-fire model neurone, modified to exhibit activity-dependent mechanisms known to be present in oxytocin neurones. The presence of a prolonged afterhyperpolarisation (AHP) was critical for the ability to mimic the observed regularisation of mean firing rate, although we also had to add a depolarising afterpotential (DAP; sometimes called an afterdepolarisation) to the model to match the observed ISI distributions. We tested this model by comparing its behaviour with the behaviour of oxytocin neurones exposed to apamin, a blocker of the medium AHP. Good fits indicate that the medium AHP actively contributes to the firing patterns of oxytocin neurones during non-bursting activity, and that oxytocin neurones generally express a DAP, even though this is usually masked by superposition of a larger AHP.

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