The online metacognitive control of decisions.

Difficult decisions typically involve mental effort, which scales with the deployment of cognitive (e.g., mnesic, attentional) resources engaged in processing decision-relevant information. But how does the brain regulate mental effort? A possibility is that the brain optimizes a resource allocation problem, whereby the amount of invested resources balances its expected cost (i.e. effort) and benefit. Our working assumption is that subjective decision confidence serves as the benefit term of the resource allocation problem, hence the "metacognitive" nature of decision control. Here, we present a computational model for the online metacognitive control of decisions or oMCD. Formally, oMCD is a Markov Decision Process that optimally solves the ensuing resource allocation problem under agnostic assumptions about the inner workings of the underlying decision system. We demonstrate how this makes oMCD a quasi-optimal control policy for a broad class of decision processes, including -but not limited to- progressive attribute integration. We disclose oMCD's main properties (in terms of choice, confidence and response time), and show that they reproduce most established empirical results in the field of value-based decision making. Finally, we discuss the possible connections between oMCD and most prominent neurocognitive theories about decision control and mental effort regulation.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

OBJECTIVE: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. METHODS: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. RESULTS: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. CONCLUSION: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

A plastic aggrecan barrier modulated by peripheral energy state gates metabolic signal access to arcuate neurons.

The hypothalamic arcuate nucleus (ARH) contains neurons vital for maintaining energy homeostasis that sense and respond to changes in blood-borne metabolic hormones. Despite its juxtaposition to the median eminence (ME), a circumventricular organ lacking a blood-brain barrier and thus exposed to circulating molecules, only a few ventral ARH neurons perceive these extravasating metabolic signals due to a poorly understood ME/ARH diffusion barrier. Here, we show in male mice that aggrecan, a perineural-net proteoglycan deposited by orexigenic ARH neurons, creates a peculiar ventrodorsal diffusion gradient. Fasting enhances aggrecan deposition more dorsally, reinforcing the diffusion barrier, particularly around neurons adjacent to fenestrated capillary loops that enter the ARH. The disruption of aggrecan deposits results in unregulated diffusion of blood-borne molecules into the ARH and impairs food intake. Our findings reveal the molecular nature and plasticity of the ME/ARH diffusion barrier, and indicate its physiological role in hypothalamic metabolic hormone sensing.

Maternal low-calorie sweetener consumption rewires hypothalamic melanocortin circuits via a gut microbial co-metabolite pathway.

The prevalence of obesity and type 2 diabetes is growing at an alarming rate, including among pregnant women. Low-calorie sweeteners (LCSs) have increasingly been used as an alternative to sugar to deliver a sweet taste without the excessive caloric load. However, there is little evidence regarding their biological effects, particularly during development. Here, we used a mouse model of maternal LCS consumption to explore the impact of perinatal LCS exposure on the development of neural systems involved in metabolic regulation. We report that adult male, but not female, offspring from both aspartame- and rebaudioside A-exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal LCS consumption reorganized hypothalamic melanocortin circuits and disrupted parasympathetic innervation of pancreatic islets in male offspring. We then identified phenylacetylglycine (PAG) as a unique metabolite that was upregulated in the milk of LCS-fed dams and the serum of their pups. Furthermore, maternal PAG treatment recapitulated some of the key metabolic and neurodevelopmental abnormalities associated with maternal LCS consumption. Together, our data indicate that maternal LCS consumption has enduring consequences on the offspring's metabolism and neural development and that these effects are likely to be mediated through the gut microbial co-metabolite PAG.

The long-lasting shadow of litter size in rodents: litter size is an underreported variable that strongly determines adult physiology.

BACKGROUND/PURPOSE: Litter size is a biological variable that strongly influences adult physiology in rodents. Despite evidence from previous decades and recent studies highlighting its major impact on metabolism, information about litter size is currently underreported in the scientific literature. Here, we urge that this important biological variable should be explicitly stated in research articles. RESULTS/CONCLUSION: Below, we briefly describe the scientific evidence supporting the impact of litter size on adult physiology and outline a series of recommendations and guidelines to be implemented by investigators, funding agencies, editors in scientific journals, and animal suppliers to fill this important gap.

Neural responses in macaque prefrontal cortex are linked to strategic exploration.

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

Molecular control of the development of hypothalamic neurons involved in metabolic regulation.

The hypothalamus is a large brain region made of nuclei and areas involved in the control of behaviors and physiological regulations. Among them, the arcuate nucleus (ARH) and the lateral hypothalamic area (LHA) contain key neuronal populations expressing the pro-opiomelanocortin (POMC), the agouti-related peptide (AgRP), and the melanin-concentrating hormone (MCH), respectively, that are involved in goal-oriented behaviors (such as feeding behavior) and glucose homeostasis. These neuronal populations are generated from distinct parts of the germinative neuroepithelium during embryonic life, and acquire their cell fate under the influence of morphogen proteins, specific transcription factors, and epigenetic modulators. POMC and MCH neuronal development continues by sending long descending axonal projections before birth under the control of axon guidance molecules such as Netrin1 and Slit2. Later, during the postnatal period, POMC and AgRP neurons develop intra-hypothalamic projections notably to the paraventricular nucleus of the hypothalamus through the influence of other axon guidance cues such as the class3 Semaphorins. Other cellular processes, such as autophagy and primary cilia function, and hormonal cues also appear critical for the proper development of POMC neurons.

Developmental programming of hypothalamic melanocortin circuits.

The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.

Using Inhibitory DREADDs to Silence LC Neurons in Monkeys.

Understanding the role of the noradrenergic nucleus locus coeruleus (LC) in cognition and behavior is critical: It is involved in several key behavioral functions such as stress and vigilance, as well as in cognitive processes such as attention and decision making. In recent years, the development of viral tools has provided a clear insight into numerous aspects of brain functions in rodents. However, given the specificity of primate brains and the key benefit of monkey research for translational applications, developing viral tools to study the LC in monkeys is essential for understanding its function and exploring potential clinical strategies. Here, we describe a pharmacogenetics approach that allows to selectively and reversibly inactivate LC neurons using Designer Receptors Exclusively Activated by Designer Drugs (DREADD). We show that the expression of the hM4Di DREADD can be restricted to noradrenergic LC neurons and that the amount of LC inhibition can be adjusted by adapting the dose of the specific DREADD activator deschloroclozapine (DCZ). Indeed, even if high doses (>0.3 mg/kg) induce a massive inhibition of LC neurons and a clear decrease in vigilance, smaller doses (<0.3 mg/kg) induce a more moderate decrease in LC activity, but it does not affect vigilance, which is more compatible with an assessment of subtle cognitive functions such as decision making and attention.