The Distributed Nature of the Internal Clock
Having examined the molecular "gears" of serotonin and dopamine, we must now zoom out to investigate the neural circuits that these monoamines modulate. The concept of a single "brain clock" has been replaced by the understanding of a distributed timing network. Two principal nodes dominate this landscape: the cortico-striatal system, associated with the Striatal Beat Frequency (SBF) model for interval timing, and the hippocampus, home to sequential "time cells" for episodic encoding. These systems are not isolated; they interact dynamically, synchronized by oscillatory rhythms that bind them into a coherent temporal processor.
Hippocampal Time Cells: A Sequence of Moments
The hippocampus, renowned for its role in spatial navigation via "place cells," also provides a map of time. "Time cells" in the CA1 region ignite sequentially during the delay period of a memory task. This sequence forms a trajectory through state space, bridging the temporal gap between discontinuous events (e.g., a tone and a trace eyeblink response). The fidelity of this sequence is critical. If the "baton pass" between cells fails, the temporal memory is lost.
Recent evidence suggests that this sequential firing is organized by the theta rhythm (4-8 Hz), a prominent oscillation in the hippocampus. Time cells exhibit "phase precession," meaning they fire at progressively earlier phases of the theta cycle as the animal moves through the time field. This phase-coding mechanism provides a way to compress long temporal intervals into the short timescale of a single neural oscillation, facilitating synaptic plasticity (STDP) and the storage of the temporal order of events. Serotonin (via 5-HT1A receptors) and dopamine (via D1/D5 receptors) strongly modulate theta power and frequency, thereby expanding or compressing the "temporal ruler" that the hippocampus applies to experience.
The Striatal Beat Frequency (SBF) Model
While the hippocampus maps "what happened when," the striatum is the engine of "how long." The Striatal Beat Frequency (SBF) model proposes a remarkably elegant solution to interval timing. It posits that the cortex contains thousands of neural oscillators firing at different frequencies. At the onset of a timed interval (t=0), these oscillators are phase-reset (synchronized) by a dopaminergic burst. As time elapses, the oscillators drift out of phase in a deterministic pattern. At any given future time point (t=Target), the specific combination of active cortical inputs creates a unique "chord" or "beat."
Striatal Medium Spiny Neurons (MSNs) act as coincidence detectors. Through reinforcement learning (mediated by dopamine), an MSN learns to recognize the specific cortical chord associated with a rewarded duration. When that pattern re-emerges, the MSN fires, signaling that the interval has elapsed. This model explains the scalar property of timing (Weber's Law) because the variance in Phase estimation grows linearly with the frequency of the oscillators. Dopamine's role here is twofold: phasically resetting the oscillators at the start and facilitating the synaptic weight changes (LTP) that allow the MSN to recognize the correct beat.
Integration: Cortico-Striatal-Hippocampal Loops
How do these two systems converse? Anatomically, there is a direct projection from the hippocampus to the ventral striatum (nucleus accumbens). This pathway allows the temporal context encoded by hippocampal time cells to influence the motivational value of waiting. Functionally, oscillatory synchronization is key. Coherent theta oscillations have been observed synchronizing the prefrontal cortex, striatum, and hippocampus during working memory and timing tasks.
We propose an integrated model where hippocampal time cells provide a "granular" representation of sequential order, essentially distinct "states" of a task, while the striatal SBF mechanism provides the "scalar" estimate of duration for each state. For example, in a multi-step task, the hippocampus might encode "Step 1, then Step 2," while the striatum encodes "Step 1 takes 5 seconds, Step 2 takes 10 seconds." Dopaminergic error signals (RPEs) likely continually recalibrate both systems: adjusting the synaptic weights of striatal coincidence detectors to refine duration estimates, and re-mapping hippocampal time fields to encompass new temporal contexts.
Excerpt from: Unveiling Temporal Dynamics Probing Serotonin and Dopamine Effects on Time Cell Function Through Integrated Approaches by Peter De Ceuster
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