Cortical plasticity declines with aging, accounting for decreased learning and memory, as well as reduced neural rehabilitation in aging brain (Singer, 1995; Park and Reuter-Lorenz, 2009). Running or other physical exercise has been suggested to improve many aspects of brain function in aging human beings, including brain plasticity (Voss et al., 2013). In aged animals, environmental enrichment has also been shown to improve learning and memory, as well as cortical plasticity; but the underlying circuit mechanisms are unknown (Vivar et al., 2013; Greifzu et al., 2014).

Our laboratory recently showed that running enhances both visual cortical responses and plasticity in adult mice (Niell and Stryker, 2010; Kaneko and Stryker, 2014). We also found that running potently activates VIP neurons in mouse primary visual cortex (V1), which in turn inhibit SST inhibitory neurons, thereby disinhibiting the excitatory pyramidal neurons and allowing them to respond more strongly to the visual stimuli for which they are selective (Fu et al., 2014). We also showed that activating VIP neurons is both sufficient and necessary for enhancing visual responses during running (Fu et al., 2014). Therefore, we set out to investigate whether the VIP-SST disinhibitory circuit, rather than general aerobic exercise, is responsible for enhanced cortical plasticity in adult mice.

To examine the function of VIP neurons in enhancing adult plasticity by running, we silenced their synaptic transmission in binocular zone of mouse V1 by injecting AAV-DIO-TetanusToxinLightChain-T2A-GFP (AAV-DIO-TeTx) into the VIP-Cre mice (Figure 1A) (Xu and Sudhof, 2013). We then compared the visual responses of stationary (running speed < 2 cm/s) and running (running speed > 5 cm/s) states, and found no significant difference (increase of peak response at preferred orientations: 4 ± 33%, mean ± SD, p = 0.74) (Figure 1—figure supplement 1), indicating that silencing the transmission of VIP neurons by TeTx abolished the effect of running on visually responsive V1 neurons, consistent with our previous report (Fu et al., 2014).

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We previously showed that running in conjunction with visual stimulation enhanced visual cortical plasticity in a mouse model of human amblyopia (Kaneko and Stryker, 2014). To test the requirement of VIP-cell synaptic transmission in this model, we first sutured closed one eyelid of VIP-Cre mice at ∼P24, before the peak of critical period, and then after 4 months injected 1 µl of AAV-DIO-TeTx or PBS (the vehicle solution for virus) into the binocular zone of V1. After an additional month, we re-opened the closed eye and allowed the animals to run on Styrofoam balls floating on air while viewing a visual stimulus 4 hr per day for 21 days, as described previously (Kaneko and Stryker, 2014). Cortical responses through two eyes were measured by an experimenter blind to the treatment with intrinsic signal imaging immediately after eye opening and every 7 days during the recovery period (Figure 1B). Intrinsic signal imaging provides a reliable and non-invasive measurement of visual cortical responses to the two eyes, permitting long-term repeated measurement of the same animal to assess plasticity (Kaneko et al., 2008). Its results have been extensively validated by electrophysiological recordings in previous studies (Kaneko et al., 2008; Kaneko and Stryker, 2014). As expected, the deprived-eye visual responses recovered well in the control PBS-injected VIP-Cre mice, and the ocular dominance index (ODI) reached a level that is similar to non-deprived animals (Figure 1C–E, black traces, compare to Figure 1 of Kaneko and Stryker (2014)). In contrast, V1 responses to the deprived eye in the AAV-DIO-TeTx injected animals recovered only modestly, even after 21 days (PBS: 1.82 ± 0.26, TeTx: 1.40 ± 0.20, p = 0.006), with an ODI significantly smaller than in the control animals (PBS: 0.249 ± 0.07, TeTx: 0.083 ± 0.02, p = 0.0004; Figure 1C–E, green traces). Indeed, the poor recovery of AAV-DIO-TeTx injected animals was similar to that of animals that did not run in our previous report (Kaneko and Stryker, 2014), despite the fact that they ran as much as PBS-injected animals (% of running time: TeTx, 67.88 ± 23.6 vs PBS, 68.14 ± 17.57; average running velocity in cm/s: TeTx, 10.78 ± 3.142 vs PBS, 9.43 ± 5.29; Figure 1—figure supplement 2). In these animals, as in all of the TeTx-treated animals described below, we noted no obvious changes in temperament or visual behavior; experimental and control animals appeared indistinguishable. Responses of the open-eye were not significantly changed in either group of animals (Figure 1D). Silencing the transmission of VIP neurons thus abolished the effect of running on adult plasticity in this mouse model of amblyopia by reducing the potentiation of deprived-eye responses during recovery.

During the critical period, 3 days of monocular deprivation (MD) is always sufficient to shift the ocular dominance by reducing the deprived-eye response. In adult mice (>3 months old), 7 days of MD is required for a reliable shift of the ocular dominance, and this shift is produced by increasing the open-eye responses (Sato and Stryker, 2008). Ocular dominance plasticity in adult mice is thus not only much slower but is also qualitatively different from that during the critical period (Sato and Stryker, 2008). To determine whether locomotion would enhance another measure of adult plasticity, we examined changes in visual responses after short-term MD in adult mice that had been reared normally (Figure 2A). As expected, 4-day MD did not significantly change the ODI or the response of either eye in adult animals housed in standard conditions (Figure 2, ‘B6 Home cage’ group). However, 4-day MD combined with daily visual stimulation and running led to enhanced plasticity, including both increases in open-eye responses and decreases in deprived-eye responses (ODI before and after MD: 0.25 ± 0.03 vs 0.09 ± 0.08, p < 0.001; closed-eye response before and after MD: 2.37 ± 0.28 vs 1.95 ± 0.34, p < 0.01; open-eye response before and after MD: 1.41 ± 0.18 vs 1.69 ± 0.25, p < 0.01; Figure 2, ‘B6 VS + run’ group). To examine the role of VIP-cell synaptic transmission in the effect of running on this measure of adult plasticity, we injected AAV-DIO-TeTx into the binocular V1 of adult VIP-Cre mice that had been reared normally and measured the changes in visual responses after 4-day MD combined with daily visual stimulation and running (Figure 2A). After silencing the synaptic transmission of VIP neurons, running in conjunction with visual stimulation still led to significant depression of the closed-eye response (2.51 ± 0.31 vs 2.23 ± 0.29, p < 0.05; Figure 2, ‘VIP-TeTx VS + run’ group) but failed to potentiate the open-eye response (1.51 ± 0.20 vs 1.53 ± 0.18, p > 0.05; Figure 2C, ‘VIP-TeTx VS + run’ group), resulting in a much smaller change of ODI after 4D-MD (0.25 ± 0.03 vs 0.18 ± 0.05, p < 0.05; Figure 2D, ‘VIP-TeTx VS + run’ group). These results indicate that the VIP neurons are specifically involved in potentiating the adult-form plasticity.

Figure 2

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We next investigated whether activating VIP neurons would be sufficient to enhance adult plasticity even without the exercise of daily running. We expressed a variant of channelrhodopsin, ChETA, in VIP neurons of binocular V1 by infecting VIP-Cre mice with AAV-DIO-ChETA-YFP (Figure 3A); we had previously shown this treatment to enhance visual responses of excitatory cells in stationary mice upon stimulation with blue light (Fu et al., 2014). We imaged baseline visual responses ∼2 weeks after viral injection. After implanting the fiber optic cannula in the binocular zone of V1, we sutured one eyelid and connected the cannula to a blue LED light source (20 Hz pulses, 2 s on, 1 s off, 4 hr each day) while the mice were housed in their home cages. No behavioral response to the optogenetic stimulus was evident during delivery. After 5-day MD in conjunction with optogenetic stimulation, we found that the visual response of the open-eye was dramatically potentiated (1.39 ± 0.19 vs 2.28 ± 0.81, p < 0.05; 64 ± 53% fold increase; Figure 3D, blue traces), significantly shifting ODI (0.22 ± 0.03 vs 0.05 ± 0.08, p < 0.05; Figure 3E, blue traces), with no significant change in the visual response of the closed eye (2.08 ± 0.12 vs 2.10 ± 0.55, p > 0.05; Figure 3C, blue traces). To rule out the possibility that the surgery procedure itself leads to enhanced plasticity, we injected VIP-Cre mice with AAV-DIO-TdTomato and subjected these control animals to the same procedure of optogenetic stimulation and 5-day MD (VIP-Tdtm group); no change was found in the open-eye response (1.77 ± 0.37 vs 1.62 ± 0.31, p > 0.05) and ODI (0.19 ± 0.06 vs 0.21 ± 0.05, p > 0.05; Figure 3C–E, red traces). Because AAV-DIO-ChETA may have labeled a small number of non-VIP neurons (Pi et al., 2013), we also examined whether stimulating non-specifically labeled, mostly pyramidal neurons would enhance adult plasticity. We injected AAV-ChETA into VIP-Cre mice and subjected the mice to the same procedure of optogenetic stimulation (pyr-ChETA group). We found no change in the visual responses to the two eyes (open eye: 1.89 ± 0.37 vs 1.78 ± 0.30, p > 0.05; closed eye: 2.64 ± 0.28 vs 2.36 ± 0.18, p > 0.05) or ODI (0.20 ± 0.02 vs 0.19 ± 0.02, p > 0.05) after 5-day MD (Figure 3C–E, magenta traces). These results therefore strongly support the hypothesis that activating VIP neurons is sufficient to enhance adult plasticity in the home cage without exercise on the trackball.

Figure 3

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Activating VIP neurons is thought to enhance visual responses by inhibiting SST neurons and thereby disinhibiting pyramidal neurons (Pfeffer et al., 2013; Fu et al., 2014). We hypothesized that silencing SST neurons directly would be as effective as activating VIP neurons for enhancing adult plasticity. To test this hypothesis, we silenced SST neurons by injecting AAV-DIO-TeTx into adult SST-Cre mice (Figure 4A) and examined visual responses and ODI after 5-day MD (Figure 4B). We found that the open-eye response in SST-Cre mice injected with AAV-DIO-TeTx (TeTx group) was significantly larger than that of either SST-Cre mice injected with AAV-DIO-TdTomato (Tdtm group) or C57BL/6J mice (B6 group) (TeTx: 1.92 ± 0.35; TdTomato: 1.42 ± 0.19; B6: 1.45 ± 0.27; Figure 4D), while the deprived-eye responses were indistinguishable between the three groups of mice (Figure 4C). Consequently, the ODI of TeTx group after 5-day MD was significantly different from those of the control Tdtm and B6 groups (TeTx: 0.06 ± 0.06, Tdtm: 0.22 ± 0.06, B6: 0.20 ± 0.07; Figure 4E). We also measured the changes in visual responses in a group of SST animals injected with AAV-DIO-TeTx before and after 5-day MD, yielding results that further confirmed that short-term silencing of SST neurons is sufficient to enhance adult plasticity by potentiating open-eye responses (Figure 4—figure supplement 1).

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The VIP-SST disinhibitory circuit has recently been found to be a potent modulator of sensory responses and to regulate cortical states by integrating long-range inputs from other brain regions (Pi et al., 2013; Fu et al., 2014; Zhang et al., 2014). The present study reveals a new function of this disinhibitory circuit in regulating cortical plasticity.

Enhancing adult plasticity has long been a topic of great interest on account of its implications for human wellbeing. Inhibitory circuits have been implicated in regulating cortical plasticity. For example, both reducing GABA production and antagonizing GABA_A receptors have been found to enhance adult plasticity in rat visual cortex, possibly by facilitating the potentiation of the input from the open eye (Harauzov et al., 2010). Chronic treatment using the antidepressant drug fluoxetine enhances adult plasticity, accompanied by reduced GABA levels in visual cortex (Maya Vetencourt et al., 2008). Our results are consistent with the idea that reduced inhibition is permissive for enhancing adult plasticity.

Removing extracellular perineuronal nets is also reported to enhance adult plasticity in rats (Pizzorusso et al., 2002; but see; Vorobyov et al., 2013). This and other findings suggest that simply destabilizing synaptic connections may enhance cortical plasticity, because reduced GABA transmission de-stabilizes GABAergic synaptic terminals (Fu et al., 2012). Transplanted GABAergic progenitor cells may create another form of instability of inhibitory circuits by making widespread new connections with host neurons and causing a second critical period of plasticity in adult mice (Southwell et al., 2010).

Extensive evidence has accumulated indicating that parvalbumin (PV)-positive fast-spiking cells play an important role in cortical plasticity (Hensch, 2005; Kuhlman et al., 2013). Our study reveals that disinhibiting pyramidal neurons by either activating VIP neurons or silencing SST neurons also enhances adult plasticity and allows potentiation of open-eye responses in V1, revealing an important role for at least these other major types of inhibitory neurons in cortical plasticity. Recent findings using transplantation of embryonic inhibitory neurons also support a role for SST neurons in cortical plasticity (Tang et al., 2014). It should be noted that there are multiple classes of SST neurons (Markram et al., 2004; Hu et al., 2013), only some of which are suppressed during locomotion (Fu et al., 2014; Reimer et al., 2014). In the present experiments, TeTx was presumably not selective in silencing the different subgroups of SST neurons.

Enhancing serotonin signaling by chronic fluoxetine treatment has also been shown to enhance adult plasticity (Maya Vetencourt et al., 2008). Exposure to an enriched environment was reported to enhance serotonin levels in rat visual cortex as well as to enhance adult plasticity (Baroncelli et al., 2010). Unlike PV and SST neurons, VIP neurons express the 5-HT₃ serotonin receptor, a channel that allows fast depolarization of neurons (Lee et al., 2010). VIP neurons also receive a direct nicotinic cholinergic input from the basal forebrain, which modulates cortical state and sensory responses (Lee and Dan, 2012; Fu et al., 2014). Therefore, the VIP-SST disinhibitory circuit is well poised as a target for manipulation of cortical plasticity by these two neuromodulators.

Adult ocular dominance plasticity in V1 consists of a potentiation of the open-eye response following MD; while critical period plasticity features an initial depression of the deprived-eye response followed by potentiation of the response to the open eye (Sato and Stryker, 2008). A number of manipulations in older animals mimic critical period plasticity in their effects on responses to the two eyes: transplantation of embryonic inhibitory neurons (Southwell et al., 2010) or acute suppression of the activity of PV neurons (Kuhlman et al., 2013) in mice, or chronic fluoxetine treatment in rats (Maya Vetencourt et al., 2008). Other manipulations, such as brief dark exposure (He et al., 2006; Stodieck et al., 2014), repeated MD (Hofer et al., 2006), visuomotor experience (Tschetter et al., 2013), or activation of Rho GTPases (Cerri et al., 2011), lead to a potentiation of open-eye responses that resembles normal adult plasticity following more prolonged MD. The present findings reveal that activation of the VIP-SST disinhibitory pathway is both necessary (Figure 1, 2) and sufficient (Figures 3, 4) for cortical plasticity that potentiates visual responses, and that aerobic exercise is neither necessary nor sufficient. Running, on the other hand, produces both potentiation of open eye responses and depression of responses to the closed eye. Running is associated not only with activation of cortical VIP neurons, but also with increases in multiple neuromodulators including serotonin and noradrenalin (Meeusen and De Meirleir, 1995), both of which have been implicated in modulating adult plasticity (Gu, 2002). It is, therefore, not surprising that enhancement of adult plasticity by locomotion is more complex than simply activating VIP-SST disinhibitory circuit, even though silencing VIP transmission abolished the effect of running on enhancing visual response (Figure 1—figure supplement 1) (Fu et al., 2014). More importantly, the present results also suggest that the potentiation of open-eye response and the depression of closed-eye response are separable from each other and are mediated by distinct mechanisms.

The difference between the plasticity produced by reducing the activity of PV- (Kuhlman et al., 2013) or SST- (Figure 4) neurons during MD suggests that different inhibitory circuits are engaged in gating distinct aspects of cortical plasticity. PV- and SST-cells innervate different compartments of pyramidal neurons and exert distinct physiological effects (Markram et al., 2004; Hu et al., 2014). For example, inhibitory synapses on dendritic spines (van Versendaal et al., 2012), which are preferentially innervated by SST neurons, are specifically lost during potentiation of the open-eye response in adult plasticity (Chiu et al., 2013). The different responses to reduced inhibition of distinct elements of the cortical circuit may be fundamental to understanding the differences between critical period and adult plasticity.

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Author details

1. Yu Fu

   Center for Integrative Neuroscience, Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   YF, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Megumi Kaneko

   For correspondence

   yufu@phy.ucsf.edu

   Competing interests

   The authors declare that no competing interests exist.

2. Megumi Kaneko

   Center for Integrative Neuroscience, Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   MK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Yu Fu

   Competing interests

   The authors declare that no competing interests exist.

3. Yunshuo Tang

   1. Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
   2. The Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, San Francisco, United States
   3. Medical Scientist Training Program, Biomedical Science Program, University of California, San Francisco, San Francisco, United States

   Contribution

   YT, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Arturo Alvarez-Buylla

   1. Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
   2. The Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, San Francisco, United States

   Contribution

   AA-B, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Michael P Stryker

   Center for Integrative Neuroscience, Department of Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   MPS, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   stryker@phy.ucsf.edu

   Competing interests

   The authors declare that no competing interests exist.

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