Dendritic Hold and Read: A Gated Mechanism for Short Term Information Storage and Retrieval

Two contrasting theories have been proposed to explain the mechanistic basis of short term memory. One theory posits that short term memory is represented by persistent neural activity supported by reverberating feedback networks. An alternate, more recent theory posits that short term memory can be supported by feedforward networks. While feedback driven memory can be implemented by well described mechanisms of synaptic plasticity, little is known of possible molecular and cellular mechanisms that can implement feedforward driven memory. Here we report such a mechanism in which the memory trace exists in the form of glutamate-bound but Mg2+-blocked NMDA receptors on the thin terminal dendrites of CA1 pyramidal neurons. Because glutamate dissociates from subsets of NMDA receptors very slowly, excitatory synaptic transmission can leave a silent residual trace that outlasts the electrical activity by hundreds of milliseconds. Read-out of the memory trace is possible if a critical level of these bound-but-blocked receptors accumulates on a dendritic branch that will allow these quasi-stable receptors to sustain a regenerative depolarization when triggered by an independent gating signal. This process is referred to here as dendritic hold and read (DHR). Because the read-out of the input is not dependent on repetition of the input and information flows in a single-pass manner, DHR can potentially support a feedforward memory architecture

A POSTSYNAPTIC ROLE FOR SHORT-TERM NEURONAL FACILITATION IN DENDRITIC SPINES

Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF), is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation (short-term postsynaptic plasticity) has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain

NMDA receptors mediate DHR.

<p>(A) The potentiation associated with DHR at an ISI of 300 ms (left) is completely eliminated after application of AP-5 (right). (B) The potentiation associated with DHR at an ISI of 200 ms (left) is also attenuated after application of the NR2B subunit selective antagonist, ifenprodil (right).</p

A distinction between DHR and PPF.

<p>(A) When the priming stimulus (blue circles) and the gating stimulus (purple circles) are separated by >50 µm, potentiation can still be observed. This separation makes it unlikely that the same set of NMDA receptors could be activated by the two stimuli. (B) As an internal control, when the priming stimulus is directed on the adjacent apical trunk (green circles) potentiation is not observed.</p

DHR is a compartmentalized phenomenon.

<p>(A) Positive DHR responses occur only when the priming (blue circles) and gating (red circles) stimuli arrive within the same individual dendritic electrical compartment (configuration a). (B) Other configuration (b–d) fail to show potentiation with comparable stimulation intensities in the same cell. Statistics of the potentiation in each configuration is provided.</p

Photolysis systems.

<p>(A) The DMD system utilizes the ability of the DLP® chip from Texas Instrument for creating user specified 2D spatial patterns. These patterns, generated by the hundreds of thousands of digital micromirrors, are used to direct and project a portion of the 355 nm output of a 1 W DPSS laser onto the dendritic arbor in the acute brain slice. Different spatial patterns can be saved by the computer and projected at video rates. (B) The holographic system utilizes the capability of the phase-only spatial light modulator (SLM) from Hamamatsu to create a hologram that projects a 3D user defined pattern onto the dendritic arbor. The light energy driving the system is a 150 mW 405 nm diode laser. Different spatial patterns can be saved by the computer and projected at video rates.</p

DHR as the elementary building block for a feedforward memory architecture.

<p>(A) The schematic illustrates one simple configuration of four hippocampal pyramidal neurons capable of temporal sequence recall. A sequence of three irregular pulses is modeled as the input (red) to a dendritic branch on cell A. A gating signal (blue), possibly a component of the theta rhythm, is a separate input onto the same dendrite. (B) If the input primes sufficient numbers of NMDARs within a time window (green dashed line) before the peak of the theta rhythm, a dendritic spike is generated which greatly increases the probability that cell A fires an action potential that is sent as input to cell B. (C) After four cycles the temporal sequence in this example is transformed into a spatial sequence encoded by activity in four adjacent neurons. Such a spatial pattern can then be recognized by classic attractor networks.</p

Feedforward memory architecture and it building blocks.

<p>(A) Plasticity mediated memory mechanisms such as paired pulse facilitation is better suited for feedback rather than feedforward memory, because they require repeating inputs. (B) The delay line is the simplest scheme for a feedforward memory network. Each element accepts the value of its upstream neighbor and transfers its current value to its downstream neighbor. When repeated iteratively the network transforms a time sequence into a spatial sequence. It is a memory mechanism because the spatial sequence accurately holds information on events that occurred in the past. (C) Crucial requirements for the building block of an effective feedforward memory are that each element be able to hold an input signal for a substantial length of time, and that the signal can then be read out without the signal being repeated. “Dendritic Hold and Read” (DHR), described here, can implement these requirements on individual dendrites. (D) The ‘shift register’ is the digital implementation of the delay line. It is used as the memory buffer at the input stage of the central processor unit (CPU) in digital computers. In this case the individual information holding element is the binary flipflop. It is a discrete time network because information is binary and is moved forward at set time intervals by a clock. The entire spatial sequence can be accessed by tapping the output of each of the flipflops simultaneously.</p

The dendritic hold and read hypothesis.

<p>(A) In the ‘dendritic hold and read’ hypothesis, information is held by the ligand-bound but Mg2+-blocked state of the NMDA receptor. To create such a population of receptors, a length of radial oblique dendrite is ‘primed’ by a low concentration of photoreleased glutamate (yellow circles). The read-out of the priming signal is postulated to be triggered by a modest ‘gating’ depolarization. This gating signal is generated by stronger focal photolysis of glutamate to activate AMPA receptors (red signal). (B) The priming stimulus need not produce any depolarization (yellow triangle). The gating stimulus (red triangle), when given in isolation, produces a 3–5 mV somatic depolarization (Control). But if the priming and gating stimuli are paired within a certain window of time (in this case ≤300 ms), an enhanced depolarization above the control response is observed (black vs. gray traces). The response to the gating stimulus when paired to the priming stimulus is called the ‘read-out’ response. (C) The ‘read-out’ response can be expressed as a function of the relative timing of priming and gating signal. The normalized response of the dendrite illustrated in panel B is shown in red. Group data for 42 dendrites is shown in black. (D) The amplitudes of ‘read-out’ responses as a function of priming intensity show a step-like behavior, also consistent with the idea that the read-out response is a local dendritic spike.</p