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Involvement of the GABAergic septo-hippocampal pathway in brain stimulation reward.

Vega-Flores G, Gruart A, Delgado-García JM - PLoS ONE (2014)

Bottom Line: The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs.We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma.These results were replicated by intrahippocampal injections of a GABAB antagonist.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurosciences, Pablo de Olavide University, Seville, Spain.

ABSTRACT
The hippocampus is a structure related to several cognitive processes, but not very much is known about its putative involvement in positive reinforcement. In its turn, the septum has been related to instrumental brain stimulation reward (BSR) by its electrical stimulation with trains of pulses. Although the anatomical relationships of the septo-hippocampal pathway are well established, the functional relationship between these structures during rewarding behaviors remains poorly understood. To explore hippocampal mechanisms involved in BSR, CA3-evoked field excitatory and inhibitory postsynaptic potentials (fEPSPs, fIPSPs) were recorded in the CA1 area during BSR in alert behaving mice. The synaptic efficiency was determined from changes in fEPSP and fIPSP amplitudes across the learning of a BSR task. The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs. Additionally, we evaluated CA1 local field potentials (LFPs) during a preference task, comparing 8-, 20-, and 100-Hz trains of septal BSR. We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma. These results were replicated by intrahippocampal injections of a GABAB antagonist. Thus, the GABAergic septo-hippocampal pathway seems to carry information involved in the encoding of reward properties, where GABAB receptors seem to play a key role. With regard to the dorsal hippocampus, fEPSPs evoked at the CA3-CA1 synapse seem to reflect the BSR learning process, while hippocampal rhythmic activities are more related to reward properties.

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Anatomical septo-hippocampal projections, electrode placement and BSR protocol.(A) Schematic representation of the main septo-hippocampal projections. Glutamatergic (red), GABAergic (blue), and cholinergic (gray) projections are indicated. Arrowheads indicate flux direction of neuronal information. (B) Animals were chronically implanted with stimulating (St.) and recording (Rec.) electrodes aimed to activate the CA3-CA1 synapse in the right dorsal hippocampus. In addition (right diagram), a bipolar stimulating electrode was implanted in the medial septum (MS). In some animals a guide cannula was also implanted in the dorsal hippocampus. Abbreviations: DG, dentate gyrus; D, L, A, dorsal, lateral, anterior; LS, lateral septum; LV, lateral ventricle; P, pyramidal cell. (C) The training protocol to learn brain stimulation reward (BSR) started with some shaping (Sh) sessions. A Sh session consisted of i) a baseline (BL) period for evoking fPSPs at the CA3-CA1 synapse with the animal located in a small box; ii) during a Skinner box (SB) session, the animal was presented with a train of stimuli to the medial septum as reinforcement, followed 40 ms later by a single pulse applied to the CA1-CA3 synapse contingent to approaches to the lever; and iii) a recovery recording (R) period under the same conditions as for BL. After Sh sessions, the animal was allowed to carry out BSR by itself (right). For this, we used the same recording periods (BL, SB, and R) as for shaping. Reinforcements could be received at a maximum rate of one/5 s. At the bottom is shown a diagram summarizing the experimental design, where squares represent the shaping training whilst circles represent BSR protocols. This key diagram is reproduced in the following figures, displaying in dark gray the corresponding stage. (D) Illustrative recordings (averaged 10 times) evoked at the CA3-CA1 synapse (arrows) and collected during baseline (BL), 40 ms after a medial septum train (SB), and recovery (R) stages. Examples of how the stage is represented in the following figures by the key diagram are shown. (E) Representative recording (averaged 10 times) collected in the CA1 area following train stimulation of the medial septum (black horizontal bar). The green arrow indicates the point where the fPSP will be evoked (40 ms delay from the train). The green arrow indicates the selected moment to evoke an fPSP at the CA3-CA1 synapse. (F) Here is illustrated how fPSPs evoked at the CA3-CA1 synapse were divided to compute the amplitude (dashed lines) of the fEPSPs (mediated by glutamate, GLU) and the late fIPSPs. The fIPSP components (A, mediated by GABAA receptors, B, mediated by GABAB receptors) and the stimulus presented to the CA3 area (white arrow) are indicated.
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pone-0113787-g001: Anatomical septo-hippocampal projections, electrode placement and BSR protocol.(A) Schematic representation of the main septo-hippocampal projections. Glutamatergic (red), GABAergic (blue), and cholinergic (gray) projections are indicated. Arrowheads indicate flux direction of neuronal information. (B) Animals were chronically implanted with stimulating (St.) and recording (Rec.) electrodes aimed to activate the CA3-CA1 synapse in the right dorsal hippocampus. In addition (right diagram), a bipolar stimulating electrode was implanted in the medial septum (MS). In some animals a guide cannula was also implanted in the dorsal hippocampus. Abbreviations: DG, dentate gyrus; D, L, A, dorsal, lateral, anterior; LS, lateral septum; LV, lateral ventricle; P, pyramidal cell. (C) The training protocol to learn brain stimulation reward (BSR) started with some shaping (Sh) sessions. A Sh session consisted of i) a baseline (BL) period for evoking fPSPs at the CA3-CA1 synapse with the animal located in a small box; ii) during a Skinner box (SB) session, the animal was presented with a train of stimuli to the medial septum as reinforcement, followed 40 ms later by a single pulse applied to the CA1-CA3 synapse contingent to approaches to the lever; and iii) a recovery recording (R) period under the same conditions as for BL. After Sh sessions, the animal was allowed to carry out BSR by itself (right). For this, we used the same recording periods (BL, SB, and R) as for shaping. Reinforcements could be received at a maximum rate of one/5 s. At the bottom is shown a diagram summarizing the experimental design, where squares represent the shaping training whilst circles represent BSR protocols. This key diagram is reproduced in the following figures, displaying in dark gray the corresponding stage. (D) Illustrative recordings (averaged 10 times) evoked at the CA3-CA1 synapse (arrows) and collected during baseline (BL), 40 ms after a medial septum train (SB), and recovery (R) stages. Examples of how the stage is represented in the following figures by the key diagram are shown. (E) Representative recording (averaged 10 times) collected in the CA1 area following train stimulation of the medial septum (black horizontal bar). The green arrow indicates the point where the fPSP will be evoked (40 ms delay from the train). The green arrow indicates the selected moment to evoke an fPSP at the CA3-CA1 synapse. (F) Here is illustrated how fPSPs evoked at the CA3-CA1 synapse were divided to compute the amplitude (dashed lines) of the fEPSPs (mediated by glutamate, GLU) and the late fIPSPs. The fIPSP components (A, mediated by GABAA receptors, B, mediated by GABAB receptors) and the stimulus presented to the CA3 area (white arrow) are indicated.

Mentions: Animals were anesthetized with 0.8–1.5% isoflurane delivered via a mouse anesthesia mask (David Kopf Instruments, Tujunga, CA, USA). The anesthetic gas was supplied from a calibrated Fluotec 5 (Fluotec-Ohmeda, Tewksbury, MA, USA) vaporizer, at a flow rate of 1–2 L/min oxygen (AstraZeneca, Madrid, Spain). Animals were implanted with bipolar stimulating electrodes in the right medial septum (0.1 mm lateral and 0.6 mm anterior to bregma, and 3.8 mm from the brain surface [27]) and in the ipsilateral Schaffer collateral/commissural pathway of the dorsal hippocampus (2 mm lateral and 1.5 mm posterior to bregma, and 1–1.5 mm from the brain surface). A recording electrode was aimed at the CA1 stratum pyramidale (1.2 mm lateral and 2.2 mm posterior to bregma, and 1–1.5 mm from the brain surface). Electrodes were made from 50 µm, Teflon-coated, tungsten wire (Advent Research, Eynsham, UK). A bare silver wire was affixed to the bone as ground. All the implanted wires were soldered to a six-pin socket (RS Amidata, Madrid, Spain) and were then fixed to the skull with dental cement (Figure 1B; see [6], [28]).


Involvement of the GABAergic septo-hippocampal pathway in brain stimulation reward.

Vega-Flores G, Gruart A, Delgado-García JM - PLoS ONE (2014)

Anatomical septo-hippocampal projections, electrode placement and BSR protocol.(A) Schematic representation of the main septo-hippocampal projections. Glutamatergic (red), GABAergic (blue), and cholinergic (gray) projections are indicated. Arrowheads indicate flux direction of neuronal information. (B) Animals were chronically implanted with stimulating (St.) and recording (Rec.) electrodes aimed to activate the CA3-CA1 synapse in the right dorsal hippocampus. In addition (right diagram), a bipolar stimulating electrode was implanted in the medial septum (MS). In some animals a guide cannula was also implanted in the dorsal hippocampus. Abbreviations: DG, dentate gyrus; D, L, A, dorsal, lateral, anterior; LS, lateral septum; LV, lateral ventricle; P, pyramidal cell. (C) The training protocol to learn brain stimulation reward (BSR) started with some shaping (Sh) sessions. A Sh session consisted of i) a baseline (BL) period for evoking fPSPs at the CA3-CA1 synapse with the animal located in a small box; ii) during a Skinner box (SB) session, the animal was presented with a train of stimuli to the medial septum as reinforcement, followed 40 ms later by a single pulse applied to the CA1-CA3 synapse contingent to approaches to the lever; and iii) a recovery recording (R) period under the same conditions as for BL. After Sh sessions, the animal was allowed to carry out BSR by itself (right). For this, we used the same recording periods (BL, SB, and R) as for shaping. Reinforcements could be received at a maximum rate of one/5 s. At the bottom is shown a diagram summarizing the experimental design, where squares represent the shaping training whilst circles represent BSR protocols. This key diagram is reproduced in the following figures, displaying in dark gray the corresponding stage. (D) Illustrative recordings (averaged 10 times) evoked at the CA3-CA1 synapse (arrows) and collected during baseline (BL), 40 ms after a medial septum train (SB), and recovery (R) stages. Examples of how the stage is represented in the following figures by the key diagram are shown. (E) Representative recording (averaged 10 times) collected in the CA1 area following train stimulation of the medial septum (black horizontal bar). The green arrow indicates the point where the fPSP will be evoked (40 ms delay from the train). The green arrow indicates the selected moment to evoke an fPSP at the CA3-CA1 synapse. (F) Here is illustrated how fPSPs evoked at the CA3-CA1 synapse were divided to compute the amplitude (dashed lines) of the fEPSPs (mediated by glutamate, GLU) and the late fIPSPs. The fIPSP components (A, mediated by GABAA receptors, B, mediated by GABAB receptors) and the stimulus presented to the CA3 area (white arrow) are indicated.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4263242&req=5

pone-0113787-g001: Anatomical septo-hippocampal projections, electrode placement and BSR protocol.(A) Schematic representation of the main septo-hippocampal projections. Glutamatergic (red), GABAergic (blue), and cholinergic (gray) projections are indicated. Arrowheads indicate flux direction of neuronal information. (B) Animals were chronically implanted with stimulating (St.) and recording (Rec.) electrodes aimed to activate the CA3-CA1 synapse in the right dorsal hippocampus. In addition (right diagram), a bipolar stimulating electrode was implanted in the medial septum (MS). In some animals a guide cannula was also implanted in the dorsal hippocampus. Abbreviations: DG, dentate gyrus; D, L, A, dorsal, lateral, anterior; LS, lateral septum; LV, lateral ventricle; P, pyramidal cell. (C) The training protocol to learn brain stimulation reward (BSR) started with some shaping (Sh) sessions. A Sh session consisted of i) a baseline (BL) period for evoking fPSPs at the CA3-CA1 synapse with the animal located in a small box; ii) during a Skinner box (SB) session, the animal was presented with a train of stimuli to the medial septum as reinforcement, followed 40 ms later by a single pulse applied to the CA1-CA3 synapse contingent to approaches to the lever; and iii) a recovery recording (R) period under the same conditions as for BL. After Sh sessions, the animal was allowed to carry out BSR by itself (right). For this, we used the same recording periods (BL, SB, and R) as for shaping. Reinforcements could be received at a maximum rate of one/5 s. At the bottom is shown a diagram summarizing the experimental design, where squares represent the shaping training whilst circles represent BSR protocols. This key diagram is reproduced in the following figures, displaying in dark gray the corresponding stage. (D) Illustrative recordings (averaged 10 times) evoked at the CA3-CA1 synapse (arrows) and collected during baseline (BL), 40 ms after a medial septum train (SB), and recovery (R) stages. Examples of how the stage is represented in the following figures by the key diagram are shown. (E) Representative recording (averaged 10 times) collected in the CA1 area following train stimulation of the medial septum (black horizontal bar). The green arrow indicates the point where the fPSP will be evoked (40 ms delay from the train). The green arrow indicates the selected moment to evoke an fPSP at the CA3-CA1 synapse. (F) Here is illustrated how fPSPs evoked at the CA3-CA1 synapse were divided to compute the amplitude (dashed lines) of the fEPSPs (mediated by glutamate, GLU) and the late fIPSPs. The fIPSP components (A, mediated by GABAA receptors, B, mediated by GABAB receptors) and the stimulus presented to the CA3 area (white arrow) are indicated.
Mentions: Animals were anesthetized with 0.8–1.5% isoflurane delivered via a mouse anesthesia mask (David Kopf Instruments, Tujunga, CA, USA). The anesthetic gas was supplied from a calibrated Fluotec 5 (Fluotec-Ohmeda, Tewksbury, MA, USA) vaporizer, at a flow rate of 1–2 L/min oxygen (AstraZeneca, Madrid, Spain). Animals were implanted with bipolar stimulating electrodes in the right medial septum (0.1 mm lateral and 0.6 mm anterior to bregma, and 3.8 mm from the brain surface [27]) and in the ipsilateral Schaffer collateral/commissural pathway of the dorsal hippocampus (2 mm lateral and 1.5 mm posterior to bregma, and 1–1.5 mm from the brain surface). A recording electrode was aimed at the CA1 stratum pyramidale (1.2 mm lateral and 2.2 mm posterior to bregma, and 1–1.5 mm from the brain surface). Electrodes were made from 50 µm, Teflon-coated, tungsten wire (Advent Research, Eynsham, UK). A bare silver wire was affixed to the bone as ground. All the implanted wires were soldered to a six-pin socket (RS Amidata, Madrid, Spain) and were then fixed to the skull with dental cement (Figure 1B; see [6], [28]).

Bottom Line: The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs.We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma.These results were replicated by intrahippocampal injections of a GABAB antagonist.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurosciences, Pablo de Olavide University, Seville, Spain.

ABSTRACT
The hippocampus is a structure related to several cognitive processes, but not very much is known about its putative involvement in positive reinforcement. In its turn, the septum has been related to instrumental brain stimulation reward (BSR) by its electrical stimulation with trains of pulses. Although the anatomical relationships of the septo-hippocampal pathway are well established, the functional relationship between these structures during rewarding behaviors remains poorly understood. To explore hippocampal mechanisms involved in BSR, CA3-evoked field excitatory and inhibitory postsynaptic potentials (fEPSPs, fIPSPs) were recorded in the CA1 area during BSR in alert behaving mice. The synaptic efficiency was determined from changes in fEPSP and fIPSP amplitudes across the learning of a BSR task. The successive BSR sessions evoked a progressive increase of the performance in inverse relationship with a decrease in the amplitude of fEPSPs, but not of fIPSPs. Additionally, we evaluated CA1 local field potentials (LFPs) during a preference task, comparing 8-, 20-, and 100-Hz trains of septal BSR. We corroborate a clear preference for BSR at 100 Hz (in comparison with BSR at 20 Hz or 8 Hz), in parallel with an increase in the spectral power of the low theta band, and a decrease in the gamma. These results were replicated by intrahippocampal injections of a GABAB antagonist. Thus, the GABAergic septo-hippocampal pathway seems to carry information involved in the encoding of reward properties, where GABAB receptors seem to play a key role. With regard to the dorsal hippocampus, fEPSPs evoked at the CA3-CA1 synapse seem to reflect the BSR learning process, while hippocampal rhythmic activities are more related to reward properties.

Show MeSH