Interneuronal mechanism for Tinbergen's hierarchical model of behavioral choice.
ABSTRACT: Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks . We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors. We provide evidence for this by investigating the interneuronal mechanisms mediating behavioral choice between two autonomous circuits that underlie whole-body withdrawal [4, 5] and feeding  in the pond snail Lymnaea. Whole-body withdrawal is a defensive reflex that is initiated by tactile contact with predators. As predicted by the hierarchical model, tactile stimuli that evoke whole-body withdrawal responses also inhibit ongoing feeding in the presence of feeding stimuli. By recording neurons from the feeding and withdrawal networks, we found no direct synaptic connections between the interneuronal and motoneuronal elements that generate the two behaviors. Instead, we discovered that behavioral choice depends on the interaction between two unique types of interneurons with asymmetrical synaptic connectivity that allows withdrawal to override feeding. One type of interneuron, the Pleuro-Buccal (PlB), is an extrinsic modulatory neuron of the feeding network that completely inhibits feeding when excited by touch-induced monosynaptic input from the second type of interneuron, Pedal-Dorsal12 (PeD12). PeD12 plays a critical role in behavioral choice by providing a synaptic pathway joining the two behavioral networks that underlies the competitive dominance of whole-body withdrawal over feeding.
Project description:Interneurons play a key role in cortical function and dysfunction, yet organization of cortical interneuronal circuitry remains poorly understood. Cortical Layer 1 (L1) contains 2 general GABAergic interneuron groups, namely single bouquet cells (SBCs) and elongated neurogliaform cells (ENGCs). SBCs predominantly make unidirectional inhibitory connections (SBC?) with L2/3 interneurons, whereas ENGCs frequently form reciprocal inhibitory and electric connections (ENGC?) with L2/3 interneurons. Here, we describe a systematic investigation of the pyramidal neuron targets of L1 neuron-led interneuronal circuits in the rat barrel cortex with simultaneous octuple whole-cell recordings and report a simple organizational scheme of the interneuronal circuits. Both SBCs? and ENGC ? L2/3 interneuronal circuits connect to L2/3 and L5, but not L6, pyramidal neurons. SBC ? L2/3 interneuronal circuits primarily inhibit the entire dendritic-somato-axonal axis of a few L2/3 and L5 pyramidal neurons located within the same column. In contrast, ENGC ? L2/3 interneuronal circuits generally inhibit the distal apical dendrite of many L2/3 and L5 pyramidal neurons across multiple columns. Finally, L1 interneuron-led circuits target distinct subcellular compartments of L2/3 and L5 pyramidal neurons in a L2/3 interneuron type-dependent manner. These results suggest that L1 neurons form canonical interneuronal circuits to control information processes in both supra- and infragranular cortical layers.
Project description:Presynaptic plasticity is known to modulate the strength of synaptic transmission. However, it remains unknown whether regulation in presynaptic neurons can evoke excitatory and inhibitory postsynaptic responses. We report here that the Caenorhabditis elegans homologs of MAST kinase, Stomatin, and Diacylglycerol kinase act in a thermosensory neuron to elicit in its postsynaptic neuron an excitatory or inhibitory response that correlates with the valence of thermal stimuli. By monitoring neural activity of the valence-coding interneuron in freely behaving animals, we show that the alteration between excitatory and inhibitory responses of the interneuron is mediated by controlling the balance of two opposing signals released from the presynaptic neuron. These alternative transmissions further generate opposing behavioral outputs necessary for the navigation on thermal gradients. Our findings suggest that valence-encoding interneuronal activity is determined by a presynaptic mechanism whereby MAST kinase, Stomatin, and Diacylglycerol kinase influence presynaptic outputs.
Project description:Sensory cues in the natural environment predict reward or punishment, important for survival. For example, the ability to detect attractive tastes indicating palatable food is essential for foraging while the recognition of inedible substrates prevents harm. While some of these sensory responses are innate, they can undergo fundamental changes due to prior experience associated with the stimulus. However, the mechanisms underlying such behavioral switching of an innate sensory response at the neuron and network levels require further investigation. We used the model learning system of Lymnaea stagnalis<sup>1-3</sup> to address the question of how an anticipated aversive outcome reverses the behavioral response to a previously effective feeding stimulus, sucrose. Key to the switching mechanism is an extrinsic inhibitory interneuron of the feeding network, PlB (pleural buccal<sup>4</sup><sup>,</sup><sup>5</sup>), which is inhibited by sucrose to allow a feeding response. After multi-trial aversive associative conditioning, pairing sucrose with strong tactile stimuli to the head, PlB's firing rate increases in response to sucrose application to the lips and the feeding response is suppressed; this learned response is reversed by the photoinactivation of a single PlB. A learning-induced persistent change in the cellular properties of PlB that results in an increase rather than a decrease in its firing rate in response to sucrose provides a neurophysiological mechanism for this behavioral switch. A key interneuron, PeD12 (Pedal-Dorsal 12), of the defensive withdrawal network<sup>5</sup><sup>,</sup><sup>6</sup> does not mediate the conditioned suppression of feeding, but its facilitated output contributes to the sensitization of the withdrawal response.
Project description:Deciphering the interneuronal circuitry is central to understanding brain functions, yet it remains a challenging task in neurobiology. Using simultaneous quadruple-octuple in vitro and dual in vivo whole-cell recordings, we found two previously unknown interneuronal circuits that link cortical layer 1-3 (L1-3) interneurons and L5 pyramidal neurons in the rat neocortex. L1 single-bouquet cells (SBCs) preferentially formed unidirectional inhibitory connections on L2/3 interneurons that inhibited the entire dendritic-somato-axonal axis of ?1% of L5 pyramidal neurons located in the same column. In contrast, L1 elongated neurogliaform cells (ENGCs) frequently formed mutual inhibitory and electric connections with L2/3 interneurons, and these L1-3 interneurons inhibited the distal apical dendrite of >60% of L5 pyramidal neurons across multiple columns. Functionally, SBC?L2/3 interneuron?L5 pyramidal neuronal circuits disinhibited and ENGC?L2/3 interneuron?L5 pyramidal neuronal circuits inhibited the initiation of dendritic complex spikes in L5 pyramidal neurons. As dendritic complex spikes can serve coincidence detection, these cortical interneuronal circuits may be essential for salience selection.
Project description:Thalamic afferents supply the cortex with sensory information by contacting both excitatory neurons and inhibitory interneurons. Interestingly, thalamic contacts with interneurons constitute such a powerful synapse that even one afferent can fire interneurons, thereby driving feedforward inhibition. However, the spatial representation of this potent synapse on interneuron dendrites is poorly understood. Using Ca imaging and electron microscopy we show that an individual thalamic afferent forms multiple contacts with the interneuronal proximal dendritic arbor, preferentially near branch points. More contacts are correlated with larger amplitude synaptic responses. Each contact, consisting of a single bouton, can release up to seven vesicles simultaneously, resulting in graded and reliable Ca transients. Computational modeling indicates that the release of multiple vesicles at each contact minimally reduces the efficiency of the thalamic afferent in exciting the interneuron. This strategy preserves the spatial representation of thalamocortical inputs across the dendritic arbor over a wide range of release conditions.
Project description:GABAergic interneurons are lost in conditions including epilepsy and CNS injury, but there are few culture models available to study their function. Towards the goal of obtaining renewable sources of GABAergic neurons, we used the molecular profile of a functionally-incomplete GABAergic precursor clone to screen 17 new clones isolated from GFP+ rat E14.5 cortex and ganglionic eminence (GE) that were generated by viral introduction of v-myc. The clones grow as neurospheres in medium with FGF2, and after withdrawal of FGF2 they exhibit varying patterns of differentiation. Transcriptional profiling and qPCR indicated that one clone (GE6) expresses high levels of mRNAs encoding Dlx1, 2, 5 and 6, glutamate decarboxylases, and presynaptic proteins including neuropeptide Y and somatostatin. Protein expression confirmed that GE6 is a progenitor with restricted differentiation giving rise mostly to neurons with GABAergic markers. In co-cultures with hippocampal neurons, GE6 neurons became electrically excitable and received both inhibitory and excitatory synapses. After withdrawal of FGF2 in cultures of GE6 alone, neurons matured to express BetaIII-tubulin, and staining for synaptophysin and vesicular GABA transporter (VGAT) were robust after 1-2 weeks of differentiation. GE6 neurons also became electrically excitable and displayed synaptic activity, but synaptic currents were carried by chloride and were blocked by bicuculline. The results suggest that the GE6 clone, which is ventrally derived from the GE, resembles GABAergic interneuron progenitors that migrate into the developing forebrain. This is the first report of a relatively stable fetal clone that can be differentiated into GABAergic interneurons with functional synapses. The purpose was to compare differentiation patterns of several different immortalized rat neural progenitor clones to identify early stages in differentiation. The cell clones studies were: GE6 (GABAergic neuronal precursor), GE2 (non-neuronal precursor, CTX8 (multipotential precursor), L2.2 (interneuronal precursor), and L2.3 (multipotential precursor). Five rat neural precursor cell clones were compared at three different time points following FGF2 withdrawal, which triggers differentiation. Three sister culture replicates were performed for each cell clone and time point, yielding 45 samples. One microarray failed so we have 44 microarray results in the dataset.
Project description:Behavioral variability often arises from variable activity in the behavior-generating neural network. The synaptic mechanisms underlying this variability are poorly understood. We show that synaptic noise, in conjunction with weak feedforward excitation, generates variable motor output in the Aplysia feeding system. A command-like neuron (CBI-10) triggers rhythmic motor programs more variable than programs triggered by CBI-2. CBI-10 weakly excites a pivotal pattern-generating interneuron (B34) strongly activated by CBI-2. The activation properties of B34 substantially account for the degree of program variability. CBI-10- and CBI-2-induced EPSPs in B34 vary in amplitude across trials, suggesting that there is synaptic noise. Computational studies show that synaptic noise is required for program variability. Further, at network state transition points when synaptic conductance is low, maximum program variability is promoted by moderate noise levels. Thus, synaptic strength and noise act together in a nonlinear manner to determine the degree of variability within a feedforward network.
Project description:Synaptic connections between identified fast-spiking (FS), parvalbumin (PV)-positive interneurons, and excitatory spiny neurons in layer 4 (L4) of the barrel cortex were investigated using patch-clamp recordings and simultaneous biocytin fillings. Three distinct clusters of FS L4 interneurons were identified based on their axonal morphology relative to the barrel column suggesting that these neurons do not constitute a homogeneous interneuron population. One L4 FS interneuron type had an axonal domain strictly confined to a L4 barrel and was therefore named "barrel-confined inhibitory interneuron" (BIn). BIns established reliable inhibitory synaptic connections with L4 spiny neurons at a high connectivity rate of 67%, of which 69% were reciprocal. Unitary IPSPs at these connections had a mean amplitude of 0.9 ± 0.8 mV with little amplitude variation and weak short-term synaptic depression. We found on average 3.7 ± 1.3 putative inhibitory synaptic contacts that were not restricted to perisomatic areas. In conclusion, we characterized a novel type of barrel cortex interneuron in the major thalamo-recipient layer 4 forming dense synaptic networks with L4 spiny neurons. These networks constitute an efficient and powerful inhibitory feedback system, which may serve to rapidly reset the barrel microcircuitry following sensory activation.
Project description:Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here we show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Our findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.
Project description:Macroscopic oscillations of different brain regions show multiple phase relationships that are persistent across time and have been implicated in routing information. While multiple cellular mechanisms influence the network oscillatory dynamics and structure the macroscopic firing motifs, one of the key questions is to identify the biophysical neuronal and synaptic properties that permit such motifs to arise. A second important issue is how the different neural activity coherence states determine the communication between the neural circuits. Here we analyse the emergence of phase-locking within bidirectionally delayed-coupled spiking circuits in which global gamma band oscillations arise from synaptic coupling among largely excitable neurons. We consider both the interneuronal (ING) and the pyramidal-interneuronal (PING) population gamma rhythms and the inter coupling targeting the pyramidal or the inhibitory neurons. Using a mean-field approach together with an exact reduction method, we reduce each spiking network to a low dimensional nonlinear system and derive the macroscopic phase resetting-curves (mPRCs) that determine how the phase of the global oscillation responds to incoming perturbations. This is made possible by the use of the quadratic integrate-and-fire model together with a Lorentzian distribution of the bias current. Depending on the type of gamma (PING vs. ING), we show that incoming excitatory inputs can either speed up the macroscopic oscillation (phase advance; type I PRC) or induce both a phase advance and a delay (type II PRC). From there we determine the structure of macroscopic coherence states (phase-locking) of two weakly synaptically-coupled networks. To do so we derive a phase equation for the coupled system which links the synaptic mechanisms to the coherence states of the system. We show that a synaptic transmission delay is a necessary condition for symmetry breaking, i.e. a non-symmetric phase lag between the macroscopic oscillations. This potentially provides an explanation to the experimentally observed variety of gamma phase-locking modes. Our analysis further shows that symmetry-broken coherence states can lead to a preferred direction of signal transfer between the oscillatory networks where this directionality also depends on the timing of the signal. Hence we suggest a causal theory for oscillatory modulation of functional connectivity between cortical circuits.