Sequential neuromodulation of Hebbian plasticity offers mechanism for effective reward-based navigation
Abstract
Spike timing-dependent plasticity (STDP) is under neuromodulatory control, which is correlated with distinct behavioral states. Previously we reported that dopamine, a reward signal, broadens the time window for synaptic potentiation and modulates the outcome of hippocampal STDP even when applied after the plasticity induction protocol (Brzosko et al., 2015). Here we demonstrate that sequential neuromodulation of STDP by acetylcholine and dopamine offers an efficacious model of reward-based navigation. Specifically, our experimental data in mouse hippocampal slices show that acetylcholine biases STDP towards synaptic depression, whilst subsequent application of dopamine converts this depression into potentiation. Incorporating this bidirectional neuromodulation-enabled correlational synaptic learning rule into a computational model yields effective navigation towards changing reward locations, as in natural foraging behavior. Thus, temporally sequenced neuromodulation of STDP enables associations to be made between actions and outcomes and also provides a possible mechanism for aligning the time scales of cellular and behavioral learning.
Article and author information
Author details
Funding
Biotechnology and Biological Sciences Research Council (BB/N019008/1)
- Ole Paulsen
Biotechnology and Biological Sciences Research Council (BB/N013956/1)
- Claudia Clopath
Engineering and Physical Sciences Research Council (Studentship)
- Sara Zannone
- Claudia Clopath
Medical Research Council (Studentship)
- Zuzanna Brzosko
- Wolfram Schultz
- Ole Paulsen
Wellcome (95495)
- Wolfram Schultz
Wellcome (200790/Z/16/Z)
- Claudia Clopath
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The research was performed under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB). The animal procedures were authorised under Project licence PPL 70/8892.
Copyright
© 2017, Brzosko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,604
- views
-
- 934
- downloads
-
- 82
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Preclinical and clinical studies show that mild to moderate hypothermia is neuroprotective in sudden cardiac arrest, ischemic stroke, perinatal hypoxia/ischemia, traumatic brain injury, and seizures. Induction of hypothermia largely involves physical cooling therapies, which induce several clinical complications, while some molecules have shown to be efficient in pharmacologically induced hypothermia (PIH). Neurotensin (NT), a 13 amino acid neuropeptide that regulates body temperature, interacts with various receptors to mediate its peripheral and central effects. NT induces PIH when administered intracerebrally. However, these effects are not observed if NT is administered peripherally, due to its rapid degradation and poor passage of the blood-brain barrier (BBB). We conjugated NT to peptides that bind the low-density lipoprotein receptor (LDLR) to generate ‘vectorized’ forms of NT with enhanced BBB permeability. We evaluated their effects in epileptic conditions following peripheral administration. One of these conjugates, VH-N412, displayed improved stability, binding potential to both the LDLR and NTSR-1, rodent/human cross-reactivity and improved brain distribution. In a mouse model of kainate (KA)-induced status epilepticus (SE), VH-N412 elicited rapid hypothermia associated with anticonvulsant effects, potent neuroprotection, and reduced hippocampal inflammation. VH-N412 also reduced sprouting of the dentate gyrus mossy fibers and preserved learning and memory skills in the treated mice. In cultured hippocampal neurons, VH-N412 displayed temperature-independent neuroprotective properties. To the best of our knowledge, this is the first report describing the successful treatment of SE with PIH. In all, our results show that vectorized NT may elicit different neuroprotection mechanisms mediated by hypothermia and/or by intrinsic neuroprotective properties.
-
- Neuroscience
The neocortex comprises anatomically discrete yet interconnected areas that are symmetrically located across the two hemispheres. Determining the logic of these macrocircuits is necessary for understanding high level brain function. Here in mice, we have mapped the areal and laminar organization of the ipsi- and contralateral cortical projection onto the primary visual, somatosensory, and motor cortices. We find that although the ipsilateral hemisphere is the primary source of cortical input, there is substantial contralateral symmetry regarding the relative contribution and areal identity of input. Laminar analysis of these input areas show that excitatory Layer 6 corticocortical cells (L6 CCs) are a major projection pathway within and between the two hemispheres. Analysis of the relative contribution of inputs from supra- (feedforward) and infragranular (feedback) layers reveals that contra-hemispheric projections reflect a dominant feedback organization compared to their ipsi-cortical counterpart. The magnitude of the interhemispheric difference in hierarchy was largest for sensory and motor projection areas compared to frontal, medial, or lateral brain areas due to a proportional increase in input from L6 neurons. L6 CCs therefore not only mediate long-range cortical communication but also reflect its inherent feedback organization.