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. 2015 Sep 16;35(37):12824-32.
doi: 10.1523/JNEUROSCI.2376-15.2015.

Modulating Hippocampal Plasticity with In Vivo Brain Stimulation

Joyce G Rohan  1 , Kim A Carhuatanta  2 , Shawn M McInturf  3 , Molly K Miklasevich  4 , Ryan Jankord  2
Affiliations

Modulating Hippocampal Plasticity with In Vivo Brain Stimulation

Joyce G Rohan et al. J Neurosci. .

Abstract

Investigations into the use of transcranial direct current stimulation (tDCS) in relieving symptoms of neurological disorders and enhancing cognitive or motor performance have exhibited promising results. However, the mechanisms by which tDCS effects brain function remain under scrutiny. We have demonstrated that in vivo tDCS in rats produced a lasting effect on hippocampal synaptic plasticity, as measured using extracellular recordings. Ex vivo preparations of hippocampal slices from rats that have been subjected to tDCS of 0.10 or 0.25 mA for 30 min followed by 30 min of recovery time displayed a robust twofold enhancement in long-term potentiation (LTP) induction accompanied by a 30% increase in paired-pulse facilitation (PPF). The magnitude of the LTP effect was greater with 0.25 mA compared with 0.10 mA stimulations, suggesting a dose-dependent relationship between tDCS intensity and its effect on synaptic plasticity. To test the persistence of these observed effects, animals were stimulated in vivo for 30 min at 0.25 mA and then allowed to return to their home cage for 24 h. Observation of the enhanced LTP induction, but not the enhanced PPF, continued 24 h after completion of 0.25 mA of tDCS. Addition of the NMDA blocker AP-5 abolished LTP in both control and stimulated rats but maintained the PPF enhancement in stimulated rats. The observation of enhanced LTP and PPF after tDCS demonstrates that non-invasive electrical stimulation is capable of modifying synaptic plasticity.

Significance statement: Researchers have used brain stimulation such as transcranial direct current stimulation on human subjects to alleviate symptoms of neurological disorders and enhance their performance. Here, using rats, we have investigated the potential mechanisms of how in vivo brain stimulation can produce such effect. We recorded directly on viable brain slices from rats after brain stimulation to detect lasting changes in pattern of neuronal activity. Our results showed that 30 min of brain stimulation in rats induced a robust enhancement in synaptic plasticity, a neuronal process critical for learning and memory. Understanding such molecular effects will lead to a better understanding of the mechanisms by which brain stimulation produces its effects on cognition and performance.

Keywords: brain stimulation; extracellular recording; hippocampus; long term potentiation; rat; tDCS.

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Figures

Figure 1.
Figure 1.
Electrode placement showing approximate size and placement on the rat skull. A, Drawing of rat skull to demonstrate the positioning of the electrode in our experimental setup. The electrode was centered on the sagittal suture and ran from 0.0 to −5.0 mm caudal to bregma. B, The Nissl-stained image (Mikula et al., 2007) shows a coronal tissue section close to the center of the electrode.
Figure 2.
Figure 2.
A, Typical positioning of our hippocampal slice in the MED64 probe, containing 64 microelectrodes arranged in an 8 × 8 array. Dotted rectangular box indicates the hippocampal area that is being recorded, whereas the solid rectangular box indicates the typical position where stimulation occurs. B, The input/output relationship was not affected by tDCS treatment (n = 3 rats, 3 slices). Data are represented as mean ± SEM. Input consists of a 5 ms biphasic stimulation waveform ranging from 10 μA (−10 to 10 μA) to 100 μA (−100 to 100 μA) in amplitude. Stimulation input was delivered through the microelectrodes within the Schaffer collateral region indicated by the solid rectangular box to stimulate CA1 neurons. Evoked extracellular potentials from the CA1 region were recorded and plotted against stimulation intensity. Data from all microelectrodes within the dotted rectangular box were averaged together to yield the output value for that particular slice. Sample voltage traces (inset) showing no obvious differences in evoked response between tDCS-treated (red) and control (black) rats. Calibration: 0.4 mV, 10 ms. Sample voltages shown were recorded from one of the microelectrodes in response to a 50 μA (top) or 40 μA (bottom) stimulation. C, Frequency of spontaneous activity was not significantly different between control and stimulated rats (n = 4 rats, 4 slices, p = 0.5). D, Sample spontaneous spike measurements in a control (top) and stimulated (bottom) rat. Calibration: 0.02 mV, 5 s.
Figure 3.
Figure 3.
Effects of tDCS on synaptic plasticity. Rats were subjected to tDCS for 30 min at 250 μA, followed by 30 min additional recovery time. A–D, Effects of tDCS on LTP. A, Graph of average, normalized slopes of evoked responses from CA1 region of hippocampus from control (Sham, black trace, n = 6 rats, 8 slices) or stimulated (tDCS, red trace, n = 6 rats, 7 slices) rats. Data are presented as means ± SEMs. Arrow denotes induction of LTP by TBS. Sample trace of evoked response before (black) and ∼30 min after (red) LTP induction by TBS is shown to the right (inset). Calibration: 0.5 mV, 5 ms. B, Graph of average, normalized amplitudes of evoked responses from CA1 region of hippocampus from control (Sham, black trace, n = 6 rats, 8 slices) or stimulated (tDCS, red trace, n = 6 rats, 7 slices) rats. Arrow denotes induction of LTP by TBS. Data are presented as means ± SEMs. C, D, Bar graph representing the average percentage LTP calculated using slopes (solid fill) and amplitudes (pattern fill) of evoked responses at 60 min after LTP induction (C) or 30 min after LTP induction (D). Significant enhancements were observed in hippocampal slices from tDCS-treated rats (red) compared with sham-treated rats (black) (slope data, p = 0.002 and 0.01 for 60 and 30 min, respectively; amplitude data, p = 0.0005 and 0.0002 for 60 and 30 min, respectively; df = 13). E, Effects of tDCS on PPF. The PPF ratio was calculated as slope (solid fill) or amplitude (pattern fill) of response resulting from the second stimulus divided by the respective slope or amplitude of response resulting from the first stimulus. There was a significant increase in PPF ratio in the CA1 region of the hippocampus from rats treated with tDCS (n = 5 rats, 6 slices) compared with that from control (n = 5 rats, 7 slices; p = 0.003 and 0.005 for slope and amplitude data, respectively; df = 65). Data are presented as means ± SEMs. *p < 0.05.
Figure 4.
Figure 4.
Effects of decreased tDCS intensity on synaptic plasticity. A–C, Schaffer collateral–CA1 LTP was significantly enhanced when rats were stimulated with 100 μA for 30 min, followed by 30 min recovery time (p < 0.05). A, A graph of fractional LTP as measured using slopes of field potentials, normalized to baseline and averaged across all animals, showing that rats subjected to tDCS had significantly greater degree of LTP (red) compared with control rats that were subjected to sham (black). Arrow denotes LTP induction by TBS. B, Bar graph showing significant increases in the average percentage LTP resulting from 30 min of 100 μA tDCS (p = 0.01 and 0.04 for slope and amplitude data, respectively; df = 10). Percentage LTP was calculated using either slopes of fEPSPs (solid fill) or amplitudes of population spikes (pattern fill) recorded in the CA1 region (n = 4 rats, 5 slices). C, Comparative bar graph indicating some dependence of tDCS-induced LTP enhancement on tDCS intensity. Average slope (solid fill) or amplitude (pattern fill) data from rats subjected to either 250 or 100 μA tDCS were normalized against their corresponding sham data. D, Rats subjected to 100 μA tDCS displayed significant enhancement of PPF as measured by slope (solid fill; p = 0.002, df = 42) or amplitude (pattern fill; p = 0.006, df = 42). *p < 0.05.
Figure 5.
Figure 5.
Effects of tDCS on synaptic plasticity assessed in 24 h. A, B, LTP was enhanced in rats 24 h after treatment with tDCS (250 μA, 30 min). A, Average, normalized slope showing enhanced LTP in tDCS-treated rats (red) compared with sham-treated rats (black). B, Bar graph of average percentage LTP showing significant enhancement of LTP in stimulated rats (red; n = 7 rats, 10 slices) compared with control (black; n = 7 rats, 8 slices, unpaired 2-tailed t test) as measured using either slope data (solid fill; p = 0.03, df = 16) or amplitude data (pattern fill; p = 0.02, df = 16). *p < 0.05. C, PPF was not altered significantly in rats 24 h after treatment with tDCS (p = 0.3–0.9). Stimuli were set at 30 (black), 40 (red), and 50 (blue) μA. Amplitude measurements were obtained to generate graphs. Slope measurements also produced no significant changes in the PPF ratio (data not shown). D, General neurotransmission property was unaltered in rats 24 h after treatment with tDCS. Average input/output relationship was similar in sham (black) and tDCS (red) rats. Sample traces of field potentials evoked by stimuli of varying intensity, as indicated. Calibration: 5 ms, 0.5 mV.
Figure 6.
Figure 6.
Effects of glutamate receptor blockers on tDCS effects. Rats were subjected to 100 μA for 30 min, followed by 30 min recovery time. A, Measured evoked response mostly mediated by iGluR as blockade of kainate, AMPA, and NMDA receptors by a mixture of 30 μm DNQX and 50 μm AP-5 diminished evoked responses from CA1 regions of the hippocampus from both stimulated (red) and control (black) rats. Bar denotes perfusion of DNQX and AP-5. Blockade of NMDA receptor only by AP-5 did not induce measureable changes in field potentials as shown by the sample recording (right inset), showing only a slight change in response size attributable to AP-5 perfusion (red) but a dramatic blockade of response attributable to both AP-5 and DNQX (blue) compared with ACSF only (black) (inset). Calibration: 10 ms, 0.5 mV. B, Blockade of NMDA receptors by AP-5 diminished LTP in both control (black) and tDCS-treated (red) rats when calculated using fEPSP slope (solid fill) or amplitude (patterned fill). C, Sample recording from tDCS-treated rat hippocampus showing initial LTP induction (first arrow) in the presence of normal ACSF, blockade of LTP induction in the presence of ACSF and AP-5 (second arrow), and normal LTP induction after wash of AP-5 (third arrow). Arrows denote LTP induction by TBS. Red bar indicates perfusion of AP-5. Black bar indicates return to perfusion of normal ACSF. D, Effect on PPF enhancement attributable to tDCS was not altered by AP-5 perfusion. In the presence of AP-5, there was still a significant enhancement of PPF (n = 2 rats, 4 slices) in rats subjected to tDCS (red) compared with sham (black) when both slopes (solid fill; p = 0.02, df = 14) or amplitudes (pattern fill; p = 0.03, df = 14) values were used for calculation. *p < 0.05.
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