In the first of a two part series, Ahn and colleagues discuss the reductionist approach pervading medicine and explain how a systems approach (as advocated by systems biology) may complement reductionism.
DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of the Dnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.
Current advances in neuromorphic engineering have made it possible to emulate complex neuronal ion channel and intracellular ionic dynamics in real time using highly compact and powerefficient complementary metal-oxide-semiconductor (CMOS) analog very-large-scale-integrated circuit technology. Recently, there has been growing interest in the neuromorphic emulation of the spike-timing-dependent plasticity (STDP) Hebbian learning rule by phenomenological modeling using CMOS, memristor or other analog devices. Here, we propose a CMOS circuit implementation of a biophysically grounded neuromorphic (iono-neuromorphic) model of synaptic plasticity that is capable of capturing both the spike rate-dependent plasticity (SRDP, of the Bienenstock-Cooper-Munro or BCM type) and STDP rules. The iono-neuromorphic model reproduces bidirectional synaptic changes with NMDA receptor-dependent and intracellular calcium-mediated long-term potentiation or long-term depression assuming retrograde endocannabinoid signaling as a second coincidence detector. Changes in excitatory or inhibitory synaptic weights are registered and stored in a nonvolatile and compact digital format analogous to the discrete insertion and removal of AMPA or GABA receptor channels. The versatile Hebbian synapse device is applicable to a variety of neuroprosthesis, brain-machine interface, neurorobotics, neuromimetic computation, machine learning, and neural-inspired adaptive control problems.iono-neuromorphic modeling | rate-based synaptic plasticity | silicon neuron | subthreshold microelectronics | VLSI circuit L earning and memory are emergent animal behaviors governed by activity-dependent neuronal adaptation rules in response to changing environments. A putative neuronal mechanism of learning and memory is Hebbian synaptic plasticity (1)-the adaptive modification of excitatory synaptic strength following paired activation of the pre-and postsynaptic neurons. Two classic paradigms for the induction of Hebbian synaptic plasticity in the mammalian hippocampus and neocortex are rate-based plasticity (2-4) [herein referred to as spike-rate-dependent plasticity (SRDP)] and spike-timing-dependent plasticity (STDP) (5-7). The SRDP induction protocols control presynaptic firing rate in order to vary the sign and magnitude of synaptic plasticity (8): a high-frequency (20-100 Hz) train of presynaptic pulses results in long-term potentiation (LTP) of the synaptic strength, whereas a low-frequency (1-5 Hz) train results in long-term depression (LTD). These protocols are consistent with the theoretical learning rule (BCM rule) proposed by Bienenstock, Cooper, and Munro (9), in which the sign and magnitude of synaptic plasticity are controlled solely by postsynaptic activity as determined by presynaptic firing rate: low postsynaptic activity weakens synaptic efficacy and high postsynaptic activity strengthens it. By contrast, the STDP induction protocol stipulates that precise timing of preand postsynaptic activities determines the direction and strength of synaptic pl...
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