a-behavioral-assay-for-investigating-role-spatial-memory-during

A Behavioral Assay for Investigating the Role of Spatial Memory During Instinctive Defense in Mice

Evolution has selected a repertoire of defensive behaviors that are essential for survival across all animal species. These behaviors are often ...

UCL Sainsbury Wellcome Centre for Neural Circuits and Behaviour

MRC Laboratory of Molecular Biology

The arrival of an action potential at a synapse triggers neurotransmitter release with a limited probability, p(r). Although p(r) is a fundamental parameter in defining synaptic efficacy, it is not uniform across all synapses, and the mechanisms by which a given synapse sets its basal release probability are unknown. By measuring p(r) at single presynaptic terminals in connected pairs of hippocampal neurons, we show that neighboring synapses on the same dendritic branch have very similar release probabilities, and p(r) is negatively correlated with the number of synapses on the branch. Increasing dendritic depolarization elicits a homeostatic decrease in p(r), and equalizing activity in the dendrite significantly reduces its variability. Our results indicate that local dendritic activity is the major determinant of basal release probability, and we suggest that this feedback regulation might be required to maintain synapses in their operational range.

Local dendritic activity sets release probability at hippocampal synapses.

Information transfer at chemical synapses occurs when vesicles fuse with the plasma membrane and release neurotransmitter. This process is stochastic and its likelihood of occurrence is a crucial factor in the regulation of signal propagation in neuronal networks. The reliability of neurotransmitter release can be highly variable: experimental data from electrophysiological, molecular and imaging studies have demonstrated that synaptic terminals can individually set their neurotransmitter release probability dynamically through local feedback regulation. This local tuning of transmission has important implications for current models of single-neuron computation.

The probability of neurotransmitter release: variability and feedback control at single synapses.

The conventional view of dendritic function is that dendrites collect synaptic input and deliver it to the soma. This view has been challenged in recent years by new results demonstrating that dendrites can act as independent processing and signalling units, performing local computations that are then broadcast to the rest of the neuron, or to other neurons via dendritic transmitter and neuromodulator release. Here we describe these findings and discuss the notion that the single dendritic branch may represent a fundamental unit of signalling in the mammalian nervous system. This view proposes that the dendritic branch is a basic organizational unit for integrating synaptic input, implementing synaptic and homeostatic plasticity, and controlling local cellular processes such as protein translation.

The single dendritic branch as a fundamental functional unit in the nervous system.

Eppendorf winner. The language of dendrites.

Instinctive defensive behaviors are essential for animal survival. Across the animal kingdom, there are sensory stimuli that innately represent threat and trigger stereotyped behaviors such as escape or freezing [1-4]. While innate behaviors are considered to be hard-wired stimulus-responses [5], they act within dynamic environments, and factors such as the properties of the threat [6-9] and its perceived intensity [1, 10, 11], access to food sources [12-14], and expectations from past experience [15, 16] have been shown to influence defensive behaviors, suggesting that their expression can be modulated. However, despite recent work [2, 4, 17-21], little is known about how flexible mouse innate defensive behaviors are and how quickly they can be modified by experience. To address this, we have investigated the dependence of escape behavior on learned knowledge about the spatial environment and how the behavior is updated when the environment changes acutely. Using behavioral assays with innately threatening visual and auditory stimuli, we show that the primary goal of escape in mice is to reach a previously memorized shelter location. Memory of the escape target can be formed in a single shelter visit lasting less than 20 s, and changes in the spatial environment lead to a rapid update of the defensive action, including changing the defensive strategy from escape to freezing. Our results show that although there are innate links between specific sensory features and defensive behavior, instinctive defensive actions are surprisingly flexible and can be rapidly updated by experience to adapt to changing spatial environments.

Rapid Spatial Learning Controls Instinctive Defensive Behavior in Mice.

Escaping from imminent danger is an instinctive behaviour that is fundamental for survival, and requires the classification of sensory stimuli as harmless or threatening. The absence of threat enables animals to forage for essential resources, but as the level of threat and potential for harm increases, they have to decide whether or not to seek safety  . Despite previous work on instinctive defensive behaviours in rodents, little is known about how the brain computes the threat level for initiating  escape. Here we show that the probability and vigour of escape in mice scale with the saliency of innate threats, and are well described by a model that computes the distance between the threat level and an escape threshold. Calcium imaging and optogenetics in the midbrain of freely behaving mice show that the activity of excitatory neurons in the deep layers of the medial superior colliculus (mSC) represents the saliency of the threat stimulus and is predictive of escape, whereas glutamatergic neurons of the dorsal periaqueductal grey (dPAG) encode exclusively the choice to escape and control escape vigour. We demonstrate a feed-forward monosynaptic excitatory connection from mSC to dPAG neurons, which is weak and unreliable-yet required for escape behaviour-and provides a synaptic threshold for dPAG activation and the initiation of escape. This threshold can be overcome by high mSC network activity because of short-term synaptic facilitation and recurrent excitation within the mSC, which amplifies and sustains synaptic drive to the dPAG. Therefore, dPAG glutamatergic neurons compute escape decisions and escape vigour using a synaptic mechanism to  threshold threat information received from the mSC, and provide a biophysical model of how the brain performs a critical behavioural computation.

Article	Year
Local dendritic activity sets release probability at hippocampal synapses. Neuron\| PubMed ID: 18701072	2008
The probability of neurotransmitter release: variability and feedback control at single synapses. Nature reviews. Neuroscience\| PubMed ID: 19377502	2009
The single dendritic branch as a fundamental functional unit in the nervous system. Current opinion in neurobiology\| PubMed ID: 20800473	2010
Eppendorf winner. The language of dendrites. Science (New York, N.Y.)\| PubMed ID: 22053040	2011
Rapid Spatial Learning Controls Instinctive Defensive Behavior in Mice. Current biology : CB\| PubMed ID: 28416117	2017
A synaptic threshold mechanism for computing escape decisions. Nature\| PubMed ID: 29925954	2018

Tiago Branco

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