Associative Hebbian synaptic plasticity in primate visual cortex

Abstract

In primates, the functional connectivity of adult primary visual cortex is susceptible to be modified by sensory training during perceptual learning. It is widely held that this type of neural plasticity might involve mechanisms like long-term potentiation (LTP) and long-term depression (LTD). NMDAR-dependent forms of LTP and LTD are particularly attractive because in rodents they can be induced in a Hebbian manner by near coincidental presynaptic and postsynaptic firing, in a paradigm termed spike timing-dependent plasticity (STDP). These fundamental properties of LTP and LTD, Hebbian induction and NMDAR dependence, have not been examined in primate cortex. Here we demonstrate these properties in the primary visual cortex of the rhesus macaque (Macaca mulatta), and also show that, like in rodents, STDP is gated by neuromodulators. These findings indicate that the cellular principles governing cortical plasticity are conserved across mammalian species, further validating the use of rodents as a model system.

Keywords: LTD; LTP; STDP; monkey.

Figure 1.

Bidirectional synaptic plasticity of the supragranular FPs evoked by layer IV stimulation. A, Example of sequential induction of LTD with LFS and LTP with TBS. FPs were recorded in the upper supragranular layers, and stimulation was applied at the upper border of the line of Gennari. Traces are averages of four consecutive FPs recorded at the indicated times. B, Average induction of LTD by LFS. C, Average induction of LTP by TBS. D, LTP and LTD depend on NMDARs. Left, Average LTP (measured 30 min after TBS) induced in 100 μm APV (black bar) and in control ACSF (Cont; white bar). Right, Average LTD (30 min after LFS) induced in 100 μm APV (black bar) and in control ACSF (white bar). E, LTD can also be induced by bath application of the M1 muscarinic agonist McN (gray bar; 10 μm, 10 min) during baseline stimulation with paired pulse (50 ms interval). Number of monkeys and experiments is indicated in parentheses.

Figure 2.

Hebbian induction of LTP and LTD in layer III pyramidal cells. A, B, Example two-pathway experiments showing homosynaptic pairing-induced LTP (A, V_m: 0 mV) and LTD (B, V_m: −40 mV). Synaptic changes were induced in the stimulated pathway (filled circles), but not in the nonstimulated pathway (open circles). Traces on top are averages of 10 consecutive responses recorded before (black) and 30 min after pairing (red). Calibration: A, B, 10 ms, 5 mV. Inset, Each tick represents 1 ms, 1 mV. C, D, NMDAR activation is required for pairing-induced LTP (C) and for pairing-induced LTD (D). Top graphs, Changes in the EPSP induced by pairing in control ACSF (filled circles) and in 100 μm APV (gray triangles). Bottom graphs, PPR and input resistance (R_in) for the control experiments (both expressed as percentage of baseline).

Figure 3.

Adrenergic gating of STDP. A, In control ACSF associative spike-timing paradigms induce neither tLTP (filled circles) nor tLTD (open circles). The diagram illustrates the conditioning paradigm (s1: stimulation of input 1, a.p: postsynaptic action potential, s2: stimulation of input 2). B, C, Bath application of agonists for β- and α1-adrenergic receptors (isoproterenol, Iso: 10 μm; Methoxamine, Mtx: 5 μm) for 10 min (gray bar) enables the induction of tLTP and tLTD. B, Example of tLTP and tLTD induced in the same cell. Traces on top are averages of 10 consecutive responses recorded before (black) and 30 min after pairing (red). Calibration: A, 50 ms, 50 mV; B, 5 ms, 5 mV. Inset, Each tick represents 1 ms, 1 mV. C, Average induction of tLTP (filled circles) and tLTD (open circles). Plotted at the bottom are PPR and input resistance (R_in), both expressed as percentage of baseline. D, Levels in GluA1 phosphorylation (percentage of control; Ctl) at the residues S845 and S831 induced by a 10 min exposure to either 10 μm Iso, 10 μm McN, or 5 μm Mtx. Example blots are shown on the top.