Interaction between theta-phase and spike-timing dependent plasticity simulates theta induced memory effects

Abstract

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between pre- and post-synaptic neurons, known as spike-timing-dependent plasticity (STDP). STDP, together with theta-phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with synchronous and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the synchronous condition, as compared to the asynchronous conditions, and was specific to theta modulated inputs. Importantly, simulations with and without each mechanism suggest that both STDP and theta-phase-dependent plasticity are necessary to replicate the findings. Together, the results indicate a role for circuit-level mechanisms, which bridges the gap between slice preparation studies and human memory.Author SummaryLong-lasting changes in synaptic connectivity between neurons have been suggested to support learning and memory processes at the cellular level in the brain. Such synaptic modifications depend on synchronous activation of neurons, which leads to generate brain oscillations. Human memory studies focus on the relationships between brain oscillations and memory processes. Direct evidence on how the cellular mechanism links to human memory behaviour is lacking. To investigate the direct link between synaptic plasticity mechanisms and human memory formation, we built a computational neural network that implements two synaptic plasticity mechanisms, which are well-established in the rodents’ hippocampus. One mechanism shows that strengthening or weakening in synaptic connectivity depends on the phases of ongoing brain oscillation at theta frequency (4 – 8 Hz), which is a dominant signal in the hippocampus. The other mechanism suggests that synaptic modification depends on the precise timing of action potentials between two neurons. Our model successfully reproduces results from rodents, as well as several human episodic memory studies which demonstrated that human associative memory performance depends on phase synchronisation in theta frequency. These findings suggest a link between specific learning mechanisms at cellular level and human memory behaviour.

Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory

“…Two groups of neurons that are simulated by an integrate-and-fire equation (cf. Parish et al, 2018; Wang et al, 2021) received two stimuli. The stimuli were modulated at 37.5 Hz with four phase offsets: 0°, 90°, 180°, and 270°, which corresponded to the visual and auditory stimuli in our experiments.…”

“…It is important to note the difference in transduction delays from the eye/ear to the brain, whereby the auditory domain reaches the cortex before the visual domain by approximately 40 ms (Di Russo et al, 2002; Picton, 2010; Schnapf et al, 1987). Therefore, we added a 40 ms delay before the auditory stimulus onset to approximate simultaneous processing in visual and auditory brain regions (Clouter et al, 2017; Wang et al, 2021). However, given that the modulation frequency of 37.5 Hz is relatively fast, just a few milliseconds difference in the transduction delays would cause the phase modulation to fail (for example, 5 ms corresponds to 67.6° at 37.5 Hz).…”

“…However, the temporal resolution in those studies is considerably lower than in the current study as stimulus inputs were modulated at theta frequency (4 Hz). We speculate that spike timing might be coordinated with theta oscillations, thus interacting with the theta-phase dependent learning mechanism (Cobb et al, 1995; Huerta & Lisman, 1995; Wang et al, 2021). The synchronous condition in the studies from Clouter et al (2017) and Wang et al (2018) allows firing at the LTP-inducing theta phase and the individual pairs of spike timing fall within the STDP window.…”

“…It is still unclear whether synapses in young and intact human brains show STDP properties similar to rodents. In the current study, we simulated our experimental procedure with a simple spiking model that implements the classic STDP learning rule (Parish et al, 2018; Wang et al, 2021). In our model, synaptic weights are strengthened if a spike of the pre-synaptic neuron arrives before a spike of the connected post-synaptic neuron, whereas the weights are weakened when this sequence is reversed.…”

“…Computational model. We adapted a computational neural network model from Wang et al (2021), which comprises two groups of neurons that represent the neo-cortex (NC) and the hippocampus. Each group of neurons was split into two subgroups that represent the visual and auditory stimulus, respectively (Nnc= 20, Nhipp=10).…”