Glucose-monitoring neurons in the mediodorsal prefrontal cortex

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<ul><li><p>Pcs University, Medical School, Institute of PhPcs, Hungary</p><p>A R T I C L E I N F O</p><p>Article history:</p><p>network. DA responsive neurons in the mdPFC were found to represent similar proportion</p><p>inhibited neurons were demonstrated to exert mainly inhibitory responses to dopamine.</p><p>B R A I N R E S E A R C H 1 4 4 4 ( 2 0 1 2 ) 3 8 4 4</p><p>Ava i l ab l e on l i ne a t www.sc i enced i r ec t . com</p><p>om1. Introduction</p><p>The prefrontal cortex (PFC) is defined as the cortex of the an-terior pole of the mammalian brain, predominantly receivingprojections from the mediodorsal thalamic nucleus (Lacroixet al., 2000; Rose and Woolsey, 1948). It has been demonstrat-ed that the prefrontal cortex is implicated in many regulatory</p><p>such as the food and fluid intake (Baldwin et al., 2002;Cardinal et al., 2002; Heidbreder and Groenewegen, 2003;Kolb, 1984, 1990; Kolb and Nonneman, 1975; Morgane et al.,2005).</p><p>The prefrontal cortex is considered to perform its complexroles via multiple interrelationships with forebrain and brain-stem areas. Anatomical studies have shown that the medialThe glucose-monitoring neurons of the mdPFC and their distinct DA sensitivity are sug-gested to be of particular significance in adaptive processes of the central feeding control.</p><p> 2012 Elsevier B.V. All rights reserved.processes, including cognitive functionsworking memory, and the control of m</p><p> Corresponding author at: Pcs University, MeE-mail address: bernadett.nagy@aok.pte.hAbbreviations: AMY, amygdala; DA, dopam</p><p>thalamic area; MB, methylene-blue; mdPFC,OBF, orbitofrontal cortex; PFC, prefrontal cor</p><p>0006-8993/$ see front matter 2012 Elseviedoi:10.1016/j.brainres.2012.01.025of all cells; the glucose-excited units were shown to display excitatory whereas the glucose-techniqueMediodorsal prefrontal cortexDopamineysiology and Neurophysiology Research Group of the Hungarian Academy of Sciences,</p><p>A B S T R A C T</p><p>The mediodorsal prefrontal cortex (mdPFC), a key structure of the limbic neural circuitry,plays important roles in the central regulation of feeding. As an integrant part of theforebrain dopamine (DA) system, it performs complex roles via interconnections withvarious brain areas where glucose-monitoring (GM) neurons have been identified. Themain goal of the present experiments was to examine whether similar GM neurons existin themediodorsal prefrontal cortex. To search for such chemosensory cells here, and to es-timate their involvement in the DA circuitry, extracellular single neuron activity of themediodorsal prefrontal cortex of anesthetized Wistar and SpragueDawley rats wasrecorded by means of tungsten wire multibarreled glass microelectrodes during microelec-trophoretic administration of D-glucose and DA. One fourth of the neurons tested changedin firing rate in response to glucose, thus, proved to be elements of the forebrain GM neuralAccepted 11 January 2012Available online 20 January 2012</p><p>Keywords:Glucose-monitoring neuronsMultibarreled microelectrophoreticBernadett Nagy, Istvn Szab, Szilrd Papp, Gbor Takcs, Csaba Szalay, Zoltn KardiResearch Report</p><p>Glucose-monitoring neurons inprefrontal cortex</p><p>www.e l sev i e r . c, decision making,otivated behaviors</p><p>dical School, Institute of Pu (B. Nagy).ine; GM, glucose-monitormediodorsal prefrontal cotex</p><p>r B.V. All rights reservedthe mediodorsal</p><p>/ l oca te /b ra i n resmediodorsal prefrontal cortex (mdPFC) has direct connectionswith limbic structures, such as the amygdala (AMY), the lateral</p><p>hysiology, Pcs, Szigeti str. 12., H-7624, Hungary. Fax: +36 72536424.</p><p>ing; GR, glucose-receptor; GS, glucose-sensitive; LHA, lateral hypo-rtex; NAcc, nucleus accumbens; NTS, nucleus of the solitary tract;</p><p>.</p></li><li><p>1971; Rolls, 1989) as well.</p><p>mdPFC neurons showed responsiveness to glucose, thus,these cells were found to be elements of the forebrain GM neu-ral network. The predominant response to glucose was inhibi-</p><p>Table 1 Effect of microelectrophoretically appliedglucose and dopamine on rat mdPFC neurons.</p><p>Glucose DA</p><p> 19 28 43 27 193 180Total 255 235</p><p>: Excitatory response; : inhibitory response; : no response.</p><p>Table 2 DA responsiveness of GM and GIS neurons inthe rat mdPFC.</p><p>DA DA DA Total</p><p>GR 7 0 8 15GS 4 10 22 36GIS 15 12 140 167Total 26 22 170 218</p><p>GIS: glucose-insensitiveneuron; GR: glucose-receptor neuron (excitedby D-glucose); GS: glucose-sensitive neuron (inhibited by D-glucose);DA: DA-nonresponsive neurons; DA: neurons facilitated by DA;</p><p>391 4 4 4 ( 2 0 1 2 ) 3 8 4 4In previous investigations, particular types of chemosen-sory cells, the so-called glucose-monitoring (GM) neurons displaying firing rate changes in response to elevation of bloodglucose level or to local microelectrophoretic administration ofD-glucose have been discovered in the above interconnectedbrain areas. Specific glucose-inhibited (glucose-sensitive, GS)neurons were identified in the LHA of rats (Oomura, 1980;Oomura et al., 1969) and later in the LHA and in the AMY of rhe-sus monkeys (Aou et al., 1984; Karadi et al., 1992; Nakano et al.,1986), and in the NTS, too (Adachi et al., 1984; Mizuno andOomura, 1984). By contrast, the NAcc and the OBF were provento contain not only GS cells but also glucose-excited (glucose-receptor, GR) neurons that are facilitated by increase of theextracellular glucose concentration (Karadi et al., 2004; Pappet al., 2007).</p><p>The GM cells were demonstrated to be influenced by cate-cholamines (Karadi et al., 1992, 2004; Lenard et al., 1995), andwith respect to this it is especially important to note that thePFC is themajor cortical target area of the ascending dopamine(DA) projections (Berger et al., 1976; Bjrklund and Lindvall,1984; Descarries et al., 1987; Ungerstedt, 1971). In addition toresponding to endogenous chemical stimuli, these chemosen-sory neurons, forming a hierarchically organized neural net-work, are also known to integrate multiple, homeostaticallyrelevant information, such as exogenous chemical and othersignals, sensory-motor, perceptual, motivational mechanisms,as well as reinforcement, learning and memory processes, tocontrol feeding and metabolic functions (Aou et al., 1984;Karadi et al., 1992, 1995, 2004; Oomura and Yoshimatsu, 1984).</p><p>Considering the above, it is supposed that the mediodorsalprefrontal cortex accomplishes its complex roles as integrantpart of the forebrain glucose-monitoring neural network. Inthe present experiments, therefore, we aimed to identify GMneurons in the mdPFC, and to examine their responsivenessto DA. To do so, extracellular single neuron activity wasrecorded in the mdPFC of anesthetized male Wistar and Spra-gueDawley rats, by means of tungsten wire multibarreledglassmicroelectrodes duringmicroelectrophoretic applicationof D-glucose and dopamine.</p><p>2. Results</p><p>Activity changes of altogether 272 neurons have been recordedin theWistar and SpragueDawley rat mdPFC. The mean spon-taneous firing rates were 2.20.2 and 2.40.3 spikes/s, respec-tively, and did not vary significantly between the twopreparations. To examine direct neuronal effect of glucose, sin-gle neuron activity was recorded during microelectrophoretichypothalamic area (LHA), the nucleus accumbens (NAcc) andthe adjacent orbitofrontal cortex (OBF) (Kita and Oomura, 1981;Kolb, 1984; Lacroix et al., 2000), all known to be important inthe central feeding control. The ratmdPFC also directly projectsto the nucleus of the solitary tract (NTS), a brainstem regionwhich integrates a number of autonomic reflexes (Terreberryand Neafsey, 1987) and is well-known as a key structure of thecentral taste information processing (Norgren and Leonard,</p><p>B R A I N R E S E A R C Hadministration of D-glucose. Results of the neurochemical stim-ulations are summarized in Table 1. Sixty-two (24.3%) of 255tion (43 of the 62 GM neurons, 69.4%), however, definitefacilitatory activity changes were also detected (19 /30.6%/ ofthe 62 neurons). The other 193 neurons (75.7%) did not changein firing rate to glucose and thus, were classified as glucose-insensitive (GIS) cells.</p><p>DA responsiveness of 235 cells was examined in the rodentmdPFC. Microiontophoretic application of DA resulted in ac-tivity changes of 55 neurons (23.4%). As Table 1 shows, in thecase of DA administration, the proportion of excitatory (28,11.9%) and inhibitory (27, 11.5%) responses was almost thesame.</p><p>Table 2 demonstrates distinct DA responsiveness ofglucose-monitoring and glucose-insensitive neurons in themdPFC. Twenty-one (41.2%) of the 51 GM units, whereas only27 (16.2%) of the 167 GIS neurons displayed discharge ratechanges to this neurotransmitter, so that DA responsivenessof the GM cells was found to be significantly higher thanthat of the glucose-insensitive units (p</p></li><li>1 440 B R A I N R E S E A R C Hdopamine administrations, higher current intensities resultedin significantly bigger firing rate changes of cells of the re-sponsive groups (p</li><li><p>1 4B R A I N R E S E A R C Hof the cells with various glucose and DA responsiveness didnot show significant difference (p=0.248 and p=0.30, respec-tively; KruskalWallis test). In addition, neither baseline firingrates nor spike durations were found to correlate with glucoseor dopamine responses (p0.213).</p><p>Burst firing characteristic of the neuronswas also examined.We have found the most burst firing cells among the neuronsinhibited by DA (64.3%), and the fewest ones (17.6% and 15%,respectively) among the cells facilitated by this catecholamineas well as among those excited by glucose (p</p></li><li><p>studywas performed in the rodent. Nevertheless, findings of thelatter gain more general significance in the light of our most re-cent microelectrophysiological experiments in the alert rhesusmonkey revealing that GR and GS neurons also exist in the pri-mate mdPFC (unpublished data).</p><p>As the othermajor finding of the present experiments, distinctdopamine sensitivity of themdPFC neurons has been elucidated:the feeding-associated GM units were shown to be more likely tochange in activity in response tomicroiontophoretically adminis-tered DA than the glucose-insensitive cells. Furthermore, the GRneuronswere found to get facilitatedwhereas theGSunitsmainlyinhibited by this catecholamine. These data are in concordancewith previous results demonstrating higher dopamine respon-siveness of the lateral hypothalamic and pallidal GM neuronscompared to that of the GIS cells, as well as the predominanceof DA induced inhibitory firing rate changes of the GS neuronsin the LHA (Karadi et al., 1992; Lenard et al., 1995).</p><p>The dense dopaminergic innervation of the PFC (Berger et al.,1976; Bjrklund and Lindvall, 1984; Descarries et al., 1987;Ungerstedt, 1971) has already been indicated to play importantroles in a variety of regulatory processes (Dalley et al., 2004;Goeders et al., 1986; Granon et al., 2000; Hedou et al., 1999;Ikemoto, 2010; Richardson and Gratton, 1998; Tzschentke,2001), including feeding-associated and tastemediated learning</p><p>and memory mechanisms as well (Baldwin et al., 2002;Gambarana et al., 2003; Hernadi et al., 2000; Touzani et al.,2010). It is especially worth noting here that food intake itselfor stimuli associated with the food have been demonstrated toincrease the extracellular DA concentration in the prefrontalcortex (Bassareo and Di Chiara, 1997; Hernandez and Hoebel,1990). These and our present data are also in agreement withthe notion that multiple regulatory functions of the mdPFC areperfectuated via interrelated complex neurochemical mecha-nisms (Morgane et al., 2005; Tzschentke, 2001).</p><p>The prefrontal cortical GM neurons are suggested to partic-ipate in the integration of several homeostatically relevantendogenous and exogenous signals. The chemosensory neu-rons at this high decision making level of the neuraxis, by uti-lizing their differential dopamine sensitivity, are supposed toplay significant role in the control of adaptive behavioral ac-tions for the well being of the organism.</p><p>Previous recording studies have suggested that cortical in-terneurons have briefer spikes than those of pyramidal neu-rons, though cortical pyramidal neurons may exhibit a widevariety of spike durations (Bartho et al., 2004; Contreras, 2004;Vigneswaran et al., 2011). In our study, examination of spike du-rations revealed no significant difference among the variousgroups of neurons, and spike durations also did not correlate</p><p>(Pith</p><p>42 B R A I N R E S E A R C H 1 4 4 4 ( 2 0 1 2 ) 3 8 4 4Fig. 4 Drawing of a brain section from the stereotaxic rat atlascortex (the number refers to the anteroposterior coordinate w</p><p>brain sectionwith themicroelectrophoreticmethylene blue labelingneuron; scale bar, 100 m.ellegrino et al., 1979) at the level of themediodorsal prefrontalreference to bregma). Inset, photomicrograph of a native</p><p>spot (pointed byarrow) of a representative glucose-monitoring</p></li><li><p>range) of appropriate polarity, was applied to eject the neuro-</p><p>paraformaldehyde (4%) and the brains were postfixed over-</p><p>their complex roles in the central regulation of food and fluid</p><p>supported by theHealthCare Scientific Council (ETT 315/2006), Na-</p><p>1 4chemicals from their respective barrels. Extracellular action po-tentials were passed into a preamplifier, a high gain amplifierincluding low and high cut filters and a window discriminatorto form standard pulses (Supertech Ltd., Hungary), and theninto a microprocessor controlled A/D converter device (CED1401 plus). The Spike 2 software package (Cambridge ElectronicDesign Ltd., United Kingdom) was used to construct frequencyhistograms and for real-time and off-line analyses. Neuronalspikes and formed pulses were continuously observed on oscil-loscopes (HAMEG HM-2037, Germany). Only the action poten-tials of spontaneously active, well-isolated cells were recorded.with glucose and dopamine responses. Relationship appears toexist, however, between neurochemical sensitivity of neuronsand their burst firing characteristics: the most burst firing cellswere found among the neurons inhibited by DA, whereas thefewest burst firing cells were observed among the cells facilitat-ed by glucose and/or the catecholamine.</p><p>To understand the significance of these above findings, andto elucidate details of complex functional attributes of themed-iodorsal prefrontal cortical glucose-monitoring neurons, includ-ing their DA receptor mechanisms, further studies are required.</p><p>4. Experimental procedures</p><p>Thirty-seven Wistar, and fifteen SpragueDawley male labora-tory rats (weighing 305380 g) were used in these experiments.Individually caged animals were kept and cared for in accor-dance with institutional, national and international regulations(BA02/2000-1/2006, Pcs University, Medical School; Law XXVIII,1998, Hungary; European Community Council Directive 86/609/EEC, 1986, 2006; NIH Guidelines, 1997). Anesthesia was inducedwith a single injection of urethane (0.6 ml/100 g body weight,25% fresh solution, Sigma, Hungary). Ratswere operated on ste-reotaxically, their scalp was incised, and a small hole wasdrilled through the skull. The microelectrode was led to themdPFC under microscopic...</p></li></ul>

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