Contextual Fear Conditioning: Connecting Brain Glucose Sensing and Hippocampal-Dependent Memories
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COMMENTARY Contextual Fear Conditioning: Connecting Brain Glucose Sensing and Hippocampal-Dependent Memories Ivan E. de Araujo E nsembles of spatial-temporal cues determine the context associated with a given episodic memory, and efficient encoding of such cues is critical for producing appropriate behavioral reactions to emotionally charged contexts. Growing evidence suggests that deficiencies in the neural mechanisms regulating contextual memory formation constitute a central component of posttraumatic stress disorder. Because the hippo- campus plays a critical role in consolidating contextual spatial- temporal cues, it is plausible to assume that impaired hippocam- pal function may be causally linked to poor trauma contextual memories and to the etiology of posttraumatic stress disorder. Rodent studies have convincingly demonstrated that glucose administration greatly enhances memory performance in numer- ous challenging tasks (1). In this issue of Biological Psychiatry, an elegant study by Glenn et al. (2) extended this principle to fear learning in humans, where evidence is provided to support the concept that glucose consumption leads to superior retention of hippocampal-dependent contextual learning—as shown by acoustic startle responses and expectancy ratings for an aversive (mild shock) unconditioned stimulus. Contextual fear conditioning thus appears to link neuronal glucose sensing to hippocampal- dependent memory formation in humans. Although glucose may improve hippocampus-dependent con- text encoding, much remains to be learned about the mechan- isms by which hippocampal neurons sense local variations in the levels of glucose. But how may neurons sense local changes in glucose availability in the first place? The so-called glucosensing neurons are cells whose membrane potential appears to be under direct control of glucose availability. Such neurons are named “glucose-excited” or “glucose-inhibited” according to whether their firing rate counts increase or decrease, respectively, in response to local changes in glucose provision (3). The mechan- isms controlling glucose-excited neuronal firing are believed to be similar to the mechanisms operating in insulin-secreting beta cells of the pancreas (4). In these cells, intracellular glucose metabolism is controlled by glucokinase (GK), the rate-limiting factor in neuronal glycolysis (4). The action of GK on glucose activates an intracellular cascade of signaling events leading to increases in cytosolic adenosine triphosphate (ATP)/adenosine diphosphate ratios, with consequent closure of ATP-sensitive potassium (KATP) channels, the net effect of which is membrane depolarization (3). These KATP channels appear to be critical for neurons to respond to local changes in glucose availability. Evidence exists favoring a central role for KATP channels in controlling hippocampal function and specifically in contextual memory formation. Expression of the KATP channel subunit Kir6.2 in the CA3 region of mice has been demonstrated, and intrahip- pocampal injections of openers and blockers of KATP channels have been shown to affect fear conditioning directly (5). Speci- fically, the KATP channel opener diazoxide impairs contextual fear memory in mice, an effect reversed by coinjection of the KATP channel blocker tolbutamide (5). Kir6.2 knockout mice were also found in the same study to be significantly impaired in contextual memory tasks, further suggesting a central role for intracellular ATP signaling in the effects now reported by Glenn et al. Different lines of evidence suggest however that glucosensing neurons might make use of GK/KATP-independent pathways to respond to local changes in glucose levels (6). For example, it has been shown that local increases in glucose concentration—at least at physiologic levels—fail to enhance cytosolic ATP levels in hypothalamus. Also, KATP channels were found to be expressed in regions of the brain not known to contain glucosensing neurons, casting doubt on the sufficiency of GK/KATP pathways for glucose sensing. Further evidence in favor of the existence nonmetabolic glucose-sensing pathways arises from the lack of expression of glucose sensor elements in a significant portion of glucosensing neurons, including relatively low levels of GK. It is also remarkable that glucose-excited neurons seem to be present in the hypothalamus of Kir6.2 knockout mice. Glucose-inhibited neurons are likewise suspected to function independently of GK- related pathways. Stimulation of ATP levels via lactate administration does not result in inhibition of hypothalamic glucose-inhibited neurons, whereas glucose appears to act via extracellular (currently undetermined) glucose sensors located on the cell membrane of lateral hypothalamic orexin neurons (7). Overall, it may be concluded from the aforementioned evidence that part of the mechanism regulating neuronal glucose sensing involves signaling pathways that do not require intracellular ATP signaling. One potential signaling apparatus linking metabolism- independent glucose sensing to changes in firing rate counts relates to the activation of taste-like membrane receptors expres- sed in certain glucose-sensing brain regions. In mammals, the transduction of sweet tastants such as glucose is mediated by the taste genes Tas1r2 and Tas1r3, whose T1R2 and T1R3 products assemble to form the heterodimeric sweet receptor T1R2/T1R3. Both Tas1r2 and Tas1r3 genes and their T1R2 and T1R3 products are expressed at high levels in the rodent hippocampus (6), where they may be optimally located to mediate the influence of glu- cose level fluctuations on hippocampal function. Consistently, the taste G protein gustducin, also required for sweet taste transduc- tion in lingual taste cells, coexpresses with T1R2 and T1R3 in hippocampal neurons (6). In favor of a potential role for sweet taste-like receptor signaling in hippocampal-dependent cognitive processes, a more recent study reported that mouse hippocampal T1R3 levels were reduced after extended exposure to the non- nutritive sweetener acesulfame potassium, an effect accompanied From the John B Pierce Laboratory and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Address correspondence to Ivan E. de Araujo, D.Phil., The John B Pierce Laboratory, 290 Congress Avenue, New Haven, CT 06519; E-mail: [email protected]. Received and accepted Mar 19, 2014. 0006-3223/$36.00 BIOL PSYCHIATRY 2014;75:834–835 http://dx.doi.org/10.1016/j.biopsych.2014.03.024 & 2014 Society of Biological Psychiatry
Transcript of Contextual Fear Conditioning: Connecting Brain Glucose Sensing and Hippocampal-Dependent Memories
COMMENTARY
Contextual Fear Conditioning: Connecting BrainGlucose Sensing and Hippocampal-DependentMemoriesIvan E. de Araujo
Ensembles of spatial-temporal cues determine the contextassociated with a given episodic memory, and efficientencoding of such cues is critical for producing appropriate
behavioral reactions to emotionally charged contexts. Growingevidence suggests that deficiencies in the neural mechanismsregulating contextual memory formation constitute a centralcomponent of posttraumatic stress disorder. Because the hippo-campus plays a critical role in consolidating contextual spatial-temporal cues, it is plausible to assume that impaired hippocam-pal function may be causally linked to poor trauma contextualmemories and to the etiology of posttraumatic stress disorder.
Rodent studies have convincingly demonstrated that glucoseadministration greatly enhances memory performance in numer-ous challenging tasks (1). In this issue of Biological Psychiatry, anelegant study by Glenn et al. (2) extended this principle to fearlearning in humans, where evidence is provided to support theconcept that glucose consumption leads to superior retention ofhippocampal-dependent contextual learning—as shown byacoustic startle responses and expectancy ratings for an aversive(mild shock) unconditioned stimulus. Contextual fear conditioningthus appears to link neuronal glucose sensing to hippocampal-dependent memory formation in humans.
Although glucose may improve hippocampus-dependent con-text encoding, much remains to be learned about the mechan-isms by which hippocampal neurons sense local variations in thelevels of glucose. But how may neurons sense local changes inglucose availability in the first place? The so-called glucosensingneurons are cells whose membrane potential appears to be underdirect control of glucose availability. Such neurons are named“glucose-excited” or “glucose-inhibited” according to whethertheir firing rate counts increase or decrease, respectively, inresponse to local changes in glucose provision (3). The mechan-isms controlling glucose-excited neuronal firing are believed tobe similar to the mechanisms operating in insulin-secreting betacells of the pancreas (4). In these cells, intracellular glucosemetabolism is controlled by glucokinase (GK), the rate-limitingfactor in neuronal glycolysis (4). The action of GK on glucoseactivates an intracellular cascade of signaling events leading toincreases in cytosolic adenosine triphosphate (ATP)/adenosinediphosphate ratios, with consequent closure of ATP-sensitivepotassium (KATP) channels, the net effect of which is membranedepolarization (3). These KATP channels appear to be critical forneurons to respond to local changes in glucose availability.
Evidence exists favoring a central role for KATP channels incontrolling hippocampal function and specifically in contextual
From the John B Pierce Laboratory and Department of Psychiatry, YaleUniversity School of Medicine, New Haven, Connecticut.
Address correspondence to Ivan E. de Araujo, D.Phil., The John BPierce Laboratory, 290 Congress Avenue, New Haven, CT 06519;E-mail: [email protected].
Received and accepted Mar 19, 2014.
0006-3223/$36.00http://dx.doi.org/10.1016/j.biopsych.2014.03.024
memory formation. Expression of the KATP channel subunit Kir6.2in the CA3 region of mice has been demonstrated, and intrahip-pocampal injections of openers and blockers of KATP channelshave been shown to affect fear conditioning directly (5). Speci-fically, the KATP channel opener diazoxide impairs contextualfear memory in mice, an effect reversed by coinjection of theKATP channel blocker tolbutamide (5). Kir6.2 knockout micewere also found in the same study to be significantly impairedin contextual memory tasks, further suggesting a central role forintracellular ATP signaling in the effects now reported byGlenn et al.
Different lines of evidence suggest however that glucosensingneurons might make use of GK/KATP-independent pathways torespond to local changes in glucose levels (6). For example, it hasbeen shown that local increases in glucose concentration—atleast at physiologic levels—fail to enhance cytosolic ATP levels inhypothalamus. Also, KATP channels were found to be expressedin regions of the brain not known to contain glucosensingneurons, casting doubt on the sufficiency of GK/KATP pathwaysfor glucose sensing. Further evidence in favor of the existencenonmetabolic glucose-sensing pathways arises from the lack ofexpression of glucose sensor elements in a significant portionof glucosensing neurons, including relatively low levels of GK.It is also remarkable that glucose-excited neurons seem to be presentin the hypothalamus of Kir6.2 knockout mice. Glucose-inhibitedneurons are likewise suspected to function independently of GK-related pathways. Stimulation of ATP levels via lactate administrationdoes not result in inhibition of hypothalamic glucose-inhibitedneurons, whereas glucose appears to act via extracellular (currentlyundetermined) glucose sensors located on the cell membrane oflateral hypothalamic orexin neurons (7). Overall, it may be concludedfrom the aforementioned evidence that part of the mechanismregulating neuronal glucose sensing involves signaling pathways thatdo not require intracellular ATP signaling.
One potential signaling apparatus linking metabolism-independent glucose sensing to changes in firing rate countsrelates to the activation of taste-like membrane receptors expres-sed in certain glucose-sensing brain regions. In mammals, thetransduction of sweet tastants such as glucose is mediated by thetaste genes Tas1r2 and Tas1r3, whose T1R2 and T1R3 productsassemble to form the heterodimeric sweet receptor T1R2/T1R3.Both Tas1r2 and Tas1r3 genes and their T1R2 and T1R3 productsare expressed at high levels in the rodent hippocampus (6), wherethey may be optimally located to mediate the influence of glu-cose level fluctuations on hippocampal function. Consistently, thetaste G protein gustducin, also required for sweet taste transduc-tion in lingual taste cells, coexpresses with T1R2 and T1R3 inhippocampal neurons (6). In favor of a potential role for sweettaste-like receptor signaling in hippocampal-dependent cognitiveprocesses, a more recent study reported that mouse hippocampalT1R3 levels were reduced after extended exposure to the non-nutritive sweetener acesulfame potassium, an effect accompanied
BIOL PSYCHIATRY 2014;75:834–835& 2014 Society of Biological Psychiatry
Commentary BIOL PSYCHIATRY 2014;75:834–835 835
by impairments in cognitive memory functions (e.g., Morris watermaze) (8). More specifically, acesulfame potassium treatmentcaused neurometabolism-related genomic and proteomic altera-tions in the hippocampus, with reductions in hippocampal T1R3being paralleled by changes in glucose transporter levels. Thesefindings are consistent with the notion that taste-like receptorsignaling acts upstream to cell-autonomous responses to nutrientavailability because knocking out taste receptors in brain cellsreduces the ability of nutrients to activate the mammalian targetof rapamycin complex 1 cascade (9). Although brain tastereceptors appear to be functional in invertebrate models (10),no direct evidence exists to date to support a causal link betweensweet taste receptor levels and hippocampal impairment. Ourcurrent understanding of how intracellular metabolic pathwaysmay affect neuronal plasticity in the hippocampus remains limited.Nevertheless, it is clear that the overall evidence so far points to acritical role for hippocampal glucose sensing in memory formation,and the apparently dissimilar molecular mechanisms of hippocam-pal neuronal plasticity and brain nutrient sensing may share morein common than ever expected before.
In conclusion, the results reported by Glenn et al. open a newavenue for accessible, noninvasive approaches to posttraumaticstress disorder and related pathologies. However, a clear under-standing of how glucose consumption may benefit contextualmemory formation ultimately depends on the characterization ofthe molecular and neuronal mechanisms linking glucose signalingto synaptic plasticity within hippocampal circuits. Much workremains to be done on that front. Future studies may involve cell-specific ablations of KATP channels or taste receptor subunitswithin molecularly identified hippocampal populations or con-versely the exogenous activation of the same populations bydesigner drugs aiming at mimicking glucose effects. Surprisingly,
dissecting glucose signaling pathways within hippocampal circuitsmay therefore reveal exactly how our brains store and recall ourmost secret fears.
The author reports no biomedical financial interests or potentialconflicts of interest.
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