In response to food reward and other pertinent events, midbrain dopaminergic neurons fire short bursts of action potentials causing a phasic release of dopamine in the prefrontal cortex (rapid and transient increases in cortical dopamine concentration). Here we apply short (2 sec) iontophoretic pulses of glutamate, GABA, dopamine and dopaminergic agonists locally, onto layer 5 pyramidal neurons in brain slices of the rat medial prefrontal cortex (PFC). Unlike glutamate and GABA, brief dopaminergic pulses had negligible effects on the resting membrane potential. However, dopamine altered action potential firing in an extremely rapid (<1s) and transient (<5min) manner, as every neuron returned to baseline in less than 5-min post-application. The physiological responses to dopamine differed markedly among individual neurons. Pyramidal neurons with a preponderance of D1-like receptor signaling respond to dopamine with a severe depression in action potential firing rate, while pyramidal neurons dominated by the D2 signaling pathway respond to dopamine with an instantaneous increase in spike production. Increasing levels of dopamine concentrations around the cell body resulted in a dose dependent response, which resembles an “inverted U curve” (Vijayraghavan et al., 2007), but this effect can easily be caused by an iontophoresis current artifact. Our present data imply that one population of PFC pyramidal neurons receiving direct synaptic contacts from midbrain dopaminergic neurons would stall during the 0.5 sec of the phasic dopamine burst. The spillover dopamine, on the other hand, would act as a positive stimulator of cortical excitability (30% increase) to all D2-receptor carrying pyramidal cells, for the next 40 seconds.
Phasic; Dopaminergic modulation; D1; D2; Dopamine receptors; Action potential
Intrinsic properties of neurons that enable them to maintain depolarized, persistently activated states in the absence of sustained input are poorly understood. In short-term memory tasks, individual prefrontal cortical (PFC) neurons are capable of maintaining persistent action potential output during delay periods between informative cues and behavioral responses. Dopamine and drugs of abuse alter PFC function and working memory possibly by modulating intrinsic neuronal properties. Here we use patch-clamp recording of layer 5 PFC pyramidal neurons to identify an action potential burst-evoked intrinsic mGluR5-mediated postsynaptic depolarization that initiates an activated state. Depolarization occurs in the absence of recurrent synaptic activity and is reduced by a postsynaptic dopamine D1/5 receptor pathway. The depolarization is substantially diminished following behavioral sensitization to cocaine; moreover the D1/5 receptor modulation is lost. We propose the burst-evoked intrinsic depolarization to be a novel form of short-term cellular memory that is modulated by dopamine and cocaine experience.
metabotropic glutamate receptor; prefrontal cortex; D1 dopamine receptor; bursting; cocaine addiction; persistent activity
Basal dendrites of neocortical pyramidal neurons are relatively short and directly attached to the cell body. This allows electrical signals arising in basal dendrites to strongly influence the neuronal output. Likewise, somatic action potentials (APs) should readily propagate back into the basilar dendritic tree to influence synaptic plasticity. Two recent studies, however, determined that sodium APs are severely attenuated in basal dendrites of cortical pyramidal cells, so that they completely fail in distal dendritic segments. Here we used the latest improvements in voltage-sensitive dye imaging technique (Zhou et al., 2007) to study AP backpropagation in basal dendrites of layer 5 pyramidal neurons of the rat prefrontal cortex. With signal-to-noise ratio greater than 15, and minimal temporal averaging (only 4 sweeps) we were able to sample AP waveforms from the very last segments of individual dendritic branches (dendritic tips). We found that in short (<150 µm) and medium range basal dendrites (150 – 200 µm in length) APs backpropagate with modest change in AP half-width or AP rise-time. The lack of substantial change in AP shape and dynamics of rise is inconsistent with the AP failure model. The lack of substantial amplitude boosting of the 3rd AP in the high-frequency burst, also suggests that in short and medium range basal dendrites backpropagating APs are not severely attenuated. Our results show that the AP failure concept does not apply in all basal dendrites of the rat prefrontal cortex. The majority of synaptic contacts in the basilar dendritic tree, actually, receive significant AP-associated electrical and calcium transients.
prefrontal cortex; pyramidal neurons; basal dendrites; action potential; backpropagation; voltage-sensitive dyes
Although primarily studied at the cell body, GABAB receptors (GABAB-Rs) are abundant at spines and dendrites of cortical pyramidal neurons, where they are positioned to influence both synaptic and dendritic function. Here we examine how GABAB-Rs modulate calcium (Ca) signals evoked by action potentials (APs) in spines and dendrites of layer 2/3 pyramidal neurons in mouse prefrontal cortex. We first use two-photon microscopy to show that GABAB-Rs inhibit AP Ca signals throughout the entire dendritic arbor of these neurons. We then use local pharmacology and GABA uncaging to show that dendritic GABAB-Rs also decrease the input resistance, shorten the AP afterdepolarization, and generate inhibitory post-synaptic potentials. However, we find that these electrophysiological effects recorded at the cell body do not correlate with the inhibition of AP Ca signals measured in spines and dendrites. Instead, we use voltage-clamp recordings to show that GABAB-Rs directly inhibit several subtypes of VSCCs in both spines and dendrites. Given the importance of VSCC-mediated Ca signals for neuronal function, our results have important implications for the functional role of dendritic GABAB-Rs in the prefrontal cortex and throughout the brain.
GABAB receptor; calcium channel; prefrontal cortex; pyramidal neuron; spine and dendrite
In the cortex, NMDA receptors (NMDARs) play a critical role in the control of synaptic plasticity processes. We have previously shown in rat visual cortex that the application of a high frequency of stimulation (HFS) protocol used to induce long-term potentiation (LTP) in layer 2/3 leads to a parallel potentiation of excitatory and inhibitory inputs received by cortical layer 5 pyramidal neurons without changing the excitation/inhibition (E/I) balance of the pyramidal neuron, indicating a homeostatic control of this parameter.
We show here that the blockade of NMDARs of the neuronal network prevents the potentiation of excitatory and inhibitory inputs and this result opens to question the role of the NMDAR isoform involved in the induction of LTP, actually being strongly debated. In P18-P23 rat cortical slices, the blockade of synaptic NR2B-containing NMDARs prevents the induction of the potentiation induced by the HFS protocol, whereas the blockade of NR2A-containing NMDARs reduced the potentiation itself. In P29-P32 cortical slices, the specific activation of NR2A-containing receptors fully ensures the potentiation of excitatory and inhibitory inputs. These results constitute the first report of a functional shift in subunit composition of NMDARs during the critical period (P12-P36) which explains the relative contribution of both NR2B- and NR2A-containing NMDARs in synaptic plasticity processes. These effects of HFS protocol are mediated by the activation of synaptic NMDARs but our results also indicate that the homeostatic control of the E/I balance is independent of NMDARs activation and is due to specialized recurrent interactions between excitatory and inhibitory networks.
2-Amino-5-phosphonovalerate; pharmacology; Animals; Cerebral Cortex; cytology; growth & development; physiology; Electric Stimulation; Electrophysiology; Neuronal Plasticity; physiology; Patch-Clamp Techniques; Pyramidal Cells; drug effects; physiology; Rats; Receptors; N-Methyl-D-Aspartate; drug effects; physiology; Synapses; physiology; Visual Cortex; cytology; growth & development; physiology
Monocular deprivation (MD) during development leads to a dramatic loss of responsiveness through the deprived eye in primary visual cortical neurons, and to degraded spatial vision (amblyopia) in all species tested so far, including rodents. Such loss of responsiveness is accompanied since the beginning by a decreased excitatory drive from the thalamo-cortical inputs. However, in the thalamorecipient layer 4, inhibitory interneurons are initially unaffected by MD and their synapses onto pyramidal cells potentiate. It remains controversial whether ocular dominance plasticity similarly or differentially affects the excitatory and inhibitory synaptic conductances driven by visual stimulation of the deprived eye and impinging onto visual cortical pyramids, after a saturating period of MD. To address this issue, we isolated visually-driven excitatory and inhibitory conductances by in vivo whole-cell recordings from layer 4 regular-spiking neurons in the primary visual cortex (V1) of juvenile rats. We found that a saturating period of MD comparably reduced visually–driven excitatory and inhibitory conductances driven by visual stimulation of the deprived eye. Also, the excitatory and inhibitory conductances underlying the synaptic responses driven by the ipsilateral, left open eye were similarly potentiated compared to controls. Multiunit recordings in layer 4 followed by spike sorting indicated that the suprathreshold loss of responsiveness and the MD-driven ocular preference shifts were similar for narrow spiking, putative inhibitory neurons and broad spiking, putative excitatory neurons. Thus, by the time the plastic response has reached a plateau, inhibitory circuits adjust to preserve the normal balance between excitation and inhibition in the cortical network of the main thalamorecipient layer.
Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.
Evidence suggests that maturation of inhibition is required for the development of plasticity to proceed in the visual cortex. However, the mechanisms by which increased inhibition promotes plasticity are not clear. Here we characterized the maturation of synaptic and intrinsic ionic properties of parvalbumin-positive interneurons, a prominent subtype of inhibitory neuron in the cortex. We used a simple integrate-and-fire model to simulate the influence of maturation of inhibition on associative plasticity rules. We simulated two input pathways that converged onto a single postsynaptic neuron. The temporal pattern of activity was constructed differently for the two pathways: one pathway represented visually-driven activity, while the other pathway represented sensory-deprived activity. In mature circuits it is established that postsynaptic cells can select for sensory-driven inputs over deprived inputs, even in the case that deprived inputs have an initial advantage in synaptic size or number. We demonstrated that maturation of inhibition was required for postsynaptic cells to appropriately select sensory-driven patterns of activity when challenged with an opponent pathway of greater size. These results outline a mechanism by which maturation of inhibition can promote plasticity in the young, a period of development that is characterized by heightened learning.
Methylphenidate (MPH) has long been used to treat attention deficit-hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically-relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established.
Juvenile (P15) and adult (P90) SD rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5 and 10 weeks following drug cessation.
1 mg/kg i.p. dose of MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults) produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (0.03 to 0.3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond.
These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.
methylphenidate; psychostimulant; ADHD; prefrontal cortex; development; neuronal excitability
Cortical pyramidal neurons show irregular in vivo action potential (AP) spiking with high-frequency bursts occurring on sparse background activity. Somatic APs can backpropagate from soma into basal and apical dendrites and locally generate dendritic calcium spikes. The critical AP frequency for generation of such dendritic calcium spikes can be very different depending on cell type or brain area involved. Previously, it was shown in vitro that calcium electrogenesis can be induced in L(ayer) 5 pyramidal neurons of prefrontal cortex (PFC). It remains an open question whether somatic burst spiking and the resulting dendritic calcium electrogenesis also occur in morphologically more compact L2/3 pyramidal neurons. Furthermore, it is not known whether critical frequencies that trigger dendritic calcium electrogenesis occur in PFC under awake conditions in vivo. Here, we addressed these issues and found that pyramidal neurons in both PFC L2/3 and L5 in awake rats spike APs in short bursts but with different probabilities. The critical frequency (CF) for calcium electrogenesis in vitro was layer-specific and lower in L5 neurons compared to L2/3. Taking the in vitro CF as a predictive measure for dendritic electrogenesis during in vivo spontaneous activity, supracritical bursts in vivo were observed in a larger fraction of L5 neurons compared to L2/3 neurons but with similar incidence within these subpopulations. Together, these results show that in PFC of awake rats, AP spiking occurs at frequencies that are relevant for dendritic calcium electrogenesis and suggest that in awake rat PFC, dendritic calcium electrogenesis may be involved in neuronal computation.
calcium electrogenesis; prefrontal cortex; action potential; high-frequency bursts; dendrites; backpropagation; in vivo; awake rats
NMDA spikes are prominent in the basal dendrites of cortical pyramidal neurons and greatly expand their ability to integrate synaptic inputs. Calcium (Ca) signals during these spikes are important for synaptic plasticity and fundamentally depend on activation of NMDA receptors. However, the factors that shape the activation of these receptors and the initiation of NMDA spikes remain unclear. Here we examine the properties of NMDA spikes in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon imaging, we demonstrate that NMDA spikes evoke large Ca signals in both postsynaptic spines and nearby dendrites. We find that the dendrite Ca signals depend on NMDA and AMPA receptors but not sodium (Na) or Ca channels. Using voltage-clamp recordings, we show that activation of dendrite NMDA receptors is enhanced by concerted synaptic activity. Blocking glutamate re-uptake further increases activation of these receptors and promotes the initiation of NMDA spikes. We conclude that glutamate spillover and recruitment of extra-synaptic receptors contribute to the initiation of NMDA spikes. These results have important implications for how synaptic activity generates both electrical and biochemical signals in dendrites and spines.
NMDA receptor; NMDA spike; glutamate spillover; prefrontal cortex; pyramidal neuron; dendrite; spine; two-photon microscopy
Inhibitory control of local neuronal circuits is critical for prefrontal cortical functioning. Modulation of inhibitory circuits by several neuromodulators has been demonstrated, but the underlying mechanisms are unclear. Neuromodulator effects on synaptic vesicle recycling have received little attention. Controversy also exists whether different pools of synaptic vesicles underlie spontaneous and activity-dependent vesicle recycling. We therefore investigated the effects of kainate receptor activation on GABA release in rat prefrontal neocortex using electrophysiological and styryl dye imaging techniques in acute neocortical slices. Electrophysiological studies demonstrated that activation of kainate receptors increased the frequency, but not the amplitude of miniature IPSCs, suggesting a presynaptic action. Using styryl dye staining and multiphoton excitation microscopy, we visualized vesicular release from inhibitory GABAergic terminals in prefrontal cortical slices and demonstrate that kainate facilitates GABA release from presynaptic terminals. Our findings also indicate the presence of two pools of GABA-containing vesicles within inhibitory terminals. Kainate modulates both pools but only when vesicles are endocytosed and exocytosed by matching protocols of dye loading, i.e., spontaneous or evoked afferent activity.
neocortex; kainate; GABA; vesicular release; FM1-43; inhibition; multiphoton excitation microscopy; brain slices
Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and post-synaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to re-balance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control.
Cortical axons contain a diverse range of voltage-activated ion channels, including Ca2+ currents. Interestingly, Ca2+ channels are not only located at presynaptic terminals, but also in the axon initial segment, suggesting a potentially important role in the regulation of action potential generation and neuronal excitability. Here, using 2-photon microscopy and whole cell patch clamp recording, we examined the properties and role of calcium channels located in the axon initial segment (AIS) and presynaptic terminals of ferret layer 5 prefrontal cortical pyramidal cells in vitro. Sub-threshold depolarization of the soma resulted in an increase in baseline and spike triggered calcium concentration in both the AIS and nearby synaptic terminals. The increase in baseline calcium concentration rose with depolarization and fell with hyperpolarization with a time constant of approximately a second and was blocked by removal of Ca2+ from the bathing medium. The increases in calcium concentration at the AIS evoked by sub- or supra-threshold-depolarization of the soma were blocked by the P/Q-channel antagonist ω-agatoxin-IVA or the N-channel antagonist ω-conotoxin-GVIA or both. The presence of these channels in the AIS pyramidal cells was confirmed with immunochemistry. Block of these channels slowed axonal action potential repolarization, apparently from reduction of the activation of a Ca2+-activated K+ current, and increased neuronal excitability. These results demonstrate novel mechanisms by which calcium currents may control the electrophysiological properties of axonal spike generation and neurotransmitter release in the neocortex.
Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits.
Neurons have a wide range of dendritic morphologies the functions of which are largely unknown. We used an optimization procedure to find neuronal morphological structures for two computational tasks: first, neuronal morphologies were selected for linearly summing excitatory synaptic potentials (EP-SPs); second, structures were selected that distinguished the temporal order of EPSPs. The solutions resembled the morphology of real neurons. In particular the neurons optimized for linear summation electrotonically separated their synapses, as found in avian nucleus laminaris neurons, and neurons optimized for spike-order detection had primary dendrites of significantly different diameter, as found in the basal and apical dendrites of cortical pyramidal neurons. This similarity makes an experimentally testable prediction of our theoretical approach, which is that pyramidal neurons can act as spike-order detectors for basal and apical inputs. The automated mapping between neuronal function and structure introduced here could allow a large catalog of computational functions to be built indexed by morphological structure.
How different is local cortical circuitry from a random network? To answer this question, we probed synaptic connections with several hundred simultaneous quadruple whole-cell recordings from layer 5 pyramidal neurons in the rat visual cortex. Analysis of this dataset revealed several nonrandom features in synaptic connectivity. We confirmed previous reports that bidirectional connections are more common than expected in a random network. We found that several highly clustered three-neuron connectivity patterns are overrepresented, suggesting that connections tend to cluster together. We also analyzed synaptic connection strength as defined by the peak excitatory postsynaptic potential amplitude. We found that the distribution of synaptic connection strength differs significantly from the Poisson distribution and can be fitted by a lognormal distribution. Such a distribution has a heavier tail and implies that synaptic weight is concentrated among few synaptic connections. In addition, the strengths of synaptic connections sharing pre- or postsynaptic neurons are correlated, implying that strong connections are even more clustered than the weak ones. Therefore, the local cortical network structure can be viewed as a skeleton of stronger connections in a sea of weaker ones. Such a skeleton is likely to play an important role in network dynamics and should be investigated further.
A dataset of hundreds of recordings in which four neurons were simultaneously monitored reveals clustered connectivity patterns among cortical neurons
In the rat dentate gyrus, pyramidal-shaped cells located on the border of the granule cell layer and the hilus are one of the most common types of γ-aminobutyric acid (GABA)-immunoreactive neurons. This study describes their electrophysiological characteristics. Membrane properties, patterns of discharge, and synaptic responses were recorded intracellularly from these cells in hippocampal slices. Each cell was identified as pyramidal-shaped by injecting the marker Neurobiotin intracellularly (n = 17).
In several respects the membrane properties of the sampled cells were similar to “fast-spiking” cells (putative inhibitory interneurons) that have been described in other areas of the hippocampus. For example, input resistance was high (mean 91.3 megohms), the membrane time constant was short (mean 7.7 ms), and there was a large afterhyperpolarization following a single action potential (mean 10.5 mV at resting potential). However, the action potentials of most pyramidal-shaped cells were not as brief (mean 1.2 ms total duration) as those of most previously described fast-spiking cells. Many pyramidal-shaped neurons had strong spike frequency adaptation relative to other fast-spiking cells. Although these latter two characteristics were apparent in the majority of the sampled cells, there were exceptional pyramidal-shaped neurons with fast action potentials and weak adaptation, demonstrating the electrophysiological variability of pyramidal-shaped cells.
Responses to outer molecular layer stimulation were composed primarily of excitatory postsynaptic potentials (EPSPs) rather than inhibitory postsynaptic potentials (IPSPs), and were usually small (EPSPs evoked at threshold were often less than 2 mV), and brief (less than 30 ms). There was variability, because in a few cells EPSPs evoked at threshold were much larger. However, regardless of EPSP amplitude, suprathreshold stimulation (up to 4 times the threshold stimulus strength) rarely evoked more than one action potential in any cell. The results suggest that stimulation of perforant path axons produces limited excitatory synaptic responses in pyramidal-shaped neurons. This may be one of the reasons why they are relatively resistant to prolonged perforant path stimulation.
The pyramidal-shaped neurons located at the base of the granule cell layer have been associated historically with a basket plexus around granule cell somata, and have been called pyramidal “basket” cells. However, basket-like endings were rare and axon collaterals outside the granule cell layer were common. Many axon collaterals were as far from the granule cell layer as the outer molecular layer and the central hilus, and antidromic action potentials could be recorded in some cells in response to weak stimulation of these areas. Taken together with the electrophysiological variability, the results indicate that these cells are physiologically heterogeneous.
interneuron; inhibition; γ-aminobutyric acid (GABA); granule cell; hippocampus
The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to
spatial cognition. Complementing hippocampal place coding, prefrontal
representations provide more abstract and hierarchically organized memories
suitable for decision making. We model a prefrontal network mediating
distributed information processing for spatial learning and action planning.
Specific connectivity and synaptic adaptation principles shape the recurrent
dynamics of the network arranged in cortical minicolumns. We show how the PFC
columnar organization is suitable for learning sparse topological-metrical
representations from redundant hippocampal inputs. The recurrent nature of the
network supports multilevel spatial processing, allowing structural features of
the environment to be encoded. An activation diffusion mechanism spreads the
neural activity through the column population leading to trajectory planning.
The model provides a functional framework for interpreting the activity of PFC
neurons recorded during navigation tasks. We illustrate the link from single
unit activity to behavioral responses. The results suggest plausible neural
mechanisms subserving the cognitive “insight” capability originally
attributed to rodents by Tolman & Honzik. Our time course analysis of neural
responses shows how the interaction between hippocampus and PFC can yield the
encoding of manifold information pertinent to spatial planning, including
prospective coding and distance-to-goal correlates.
We study spatial cognition, a high-level brain function based upon the ability to
elaborate mental representations of the environment supporting goal-oriented
navigation. Spatial cognition involves parallel information processing across a
distributed network of interrelated brain regions. Depending on the complexity
of the spatial navigation task, different neural circuits may be primarily
involved, corresponding to different behavioral strategies. Navigation planning,
one of the most flexible strategies, is based on the ability to prospectively
evaluate alternative sequences of actions in order to infer optimal trajectories
to a goal. The hippocampal formation and the prefrontal cortex are two neural
substrates likely involved in navigation planning. We adopt a computational
modeling approach to show how the interactions between these two brain areas may
lead to learning of topological representations suitable to mediate action
planning. Our model suggests plausible neural mechanisms subserving the
cognitive spatial capabilities attributed to rodents. We provide a functional
framework for interpreting the activity of prefrontal and hippocampal neurons
recorded during navigation tasks. Akin to integrative neuroscience approaches,
we illustrate the link from single unit activity to behavioral responses while
solving spatial learning tasks.
We describe a Bayesian inference scheme for quantifying the active physiology of neuronal ensembles using local field recordings of synaptic potentials. This entails the inversion of a generative neural mass model of steady-state spectral activity. The inversion uses Expectation Maximization (EM) to furnish the posterior probability of key synaptic parameters and the marginal likelihood of the model itself. The neural mass model embeds prior knowledge pertaining to both the anatomical [synaptic] circuitry and plausible trajectories of neuronal dynamics. This model comprises a population of excitatory pyramidal cells, under local interneuron inhibition and driving excitation from layer IV stellate cells. Under quasi-stationary assumptions, the model can predict the spectral profile of local field potentials (LFP). This means model parameters can be optimised given real electrophysiological observations. The validity of inferences about synaptic parameters is demonstrated using simulated data and experimental recordings from the medial prefrontal cortex of control and isolation-reared Wistar rats. Specifically, we examined the maximum a posteriori estimates of parameters describing synaptic function in the two groups and tested predictions derived from concomitant microdialysis measures. The modelling of the LFP recordings revealed (i) a sensitization of post-synaptic excitatory responses, particularly marked in pyramidal cells, in the medial prefrontal cortex of socially isolated rats and (ii) increased neuronal adaptation. These inferences were consistent with predictions derived from experimental microdialysis measures of extracellular glutamate levels.
dynamic systems; dynamic causal modelling; schizophrenia; glutamate; GABA
Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4--5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs.
autism; EPSC; Fragile X; hyperconnectivity; prefrontal cortex
Layer 2/3 (L2/3) pyramidal cells receive excitatory afferent input both from neighbouring pyramidal cells and from cortical and subcortical regions. The efficacy of these excitatory synaptic inputs is modulated by spike timing–dependent plasticity (STDP). Here we report that synaptic connections between L2/3 pyramidal cell pairs are located proximal to the soma, at sites overlapping those of excitatory inputs from other cortical layers. Nevertheless, STDP at L2/3 pyramidal to pyramidal cell connections showed fundamental differences from known STDP rules at these neighbouring contacts. Coincident low-frequency pre- and postsynaptic activation evoked only LTD, independent of the order of the pre- and postsynaptic cell firing. This symmetric anti-Hebbian STDP switched to a typical Hebbian learning rule if a postsynaptic action potential train occurred prior to the presynaptic stimulation. Receptor dependence of LTD and LTP induction and their pre- or postsynaptic loci also differed from those at other L2/3 pyramidal cell excitatory inputs. Overall, we demonstrate a novel means to switch between STDP rules dependent on the history of postsynaptic activity. We also highlight differences in STDP at excitatory synapses onto L2/3 pyramidal cells which allow for input specific modulation of synaptic gain.
neocortex; pyramidal cells; synaptic plasticity
Inter-pyramidal synaptic connections are characterized by a wide range of EPSP amplitudes. Although repeatedly observed at different brain regions and across layers, little is known about the synaptic characteristics that contribute to this wide range. In particular, the range could potentially be accounted for by differences in all three parameters of the quantal model of synaptic transmission, i.e. the number of release sites, release probability and quantal size. Here, we present a rigorous statistical analysis of the transmission properties of excitatory synaptic connections between layer-5 pyramidal neurons of the somato-sensory cortex. Our central finding is that the EPSP amplitude is strongly correlated with the number of estimated release sites, but not with the release probability or quantal size. In addition, we found that the number of release sites can be more than an order of magnitude higher than the typical number of synaptic contacts for this type of connection. Our findings indicate that transmission at stronger synaptic connections is mediated by multiquantal release from their synaptic contacts. We propose that modulating the number of release sites could be an important mechanism in regulating neocortical synaptic transmission.
synaptic transmission; quantal analysis; neocortex; short-term depression
In the primate prefrontal cortex (PFC), the functional maturation of the synaptic connections of certain classes of GABA neurons is very complex. For example, the levels of both pre- and post-synaptic proteins that regulate GABA neurotransmission from the chandelier class of cortical interneurons to the axon initial segment (AIS) of pyramidal neurons undergo marked changes during both the perinatal period and adolescence in the monkey PFC. In order to understand the potential molecular mechanisms associated with these developmental refinements, we quantified the relative densities, laminar distributions, and lengths of pyramidal neuron AIS immunoreactive for ankyrin-G, ßIV spectrin, or gephyrin, three proteins involved in regulating synapse structure and receptor localization, in the PFC of rhesus monkeys ranging in age from birth through adulthood. Ankyrin-G- and ßIV spectrin-labeled AIS declined in density and length during the first six months postnatal, but then remained stable through adolescence and into adulthood. In contrast, the density of gephyrin-labeled AIS was stable until approximately 15 months of age and then markedly declined during adolescence. Thus, molecular determinants of the structural features that define GABA inputs to pyramidal neuron AIS in monkey PFC undergo distinct developmental trajectories with different types of changes occurring during the perinatal period and adolescence. In concert with previous data, these findings reveal a two-phase developmental process of GABAergic synaptic stability and GABA neurotransmission at chandelier cell inputs to pyramidal neurons that likely contributes to the protracted maturation of behaviors mediated by primate PFC circuitry.
ankyrin-G; ßIV spectrin; chandelier cell; GABAA receptor; gephyrin; working memory
Frequency and timing of action potential discharge are key elements for coding and transfer of information between neurons. The nature and location of the synaptic contacts, the biophysical parameters of the receptor-operated channels and their kinetics of activation are major determinants of the firing behaviour of each individual neuron. Ultimately the intrinsic excitability of each neuron determines the input-output function. Here we evaluate the influence of spontaneous GABAergic synaptic activity on the timing of action potentials in Layer 2/3 pyramidal neurones in acute brain slices from the somatosensory cortex of young rats. Somatic dynamic current injection to mimic synaptic input events was employed, together with a simple computational model that reproduce subthreshold membrane properties. Besides the well-documented control of neuronal excitability, spontaneous background GABAergic activity has a major detrimental effect on spike timing. In fact, GABAA receptors tune the relationship between the excitability and fidelity of pyramidal neurons via a postsynaptic (the reversal potential for GABAA activity) and a presynaptic (the frequency of spontaneous activity) mechanism. GABAergic activity can decrease or increase the excitability of pyramidal neurones, depending on the difference between the reversal potential for GABAA receptors and the threshold for action potential. In contrast, spike time jitter can only be increased proportionally to the difference between these two membrane potentials. Changes in excitability by background GABAergic activity can therefore only be associated with deterioration of the reliability of spike timing.
Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.
► Activation of a sensory cortex causes hyperpolarizing responses in neighboring ones ► Sound activates GABAergic synapses onto layer 2/3 pyramids of the visual cortex ► Sound-driven inhibition is due to activation of few cells in layer 5 of visual cortex ► Sound-driven inhibition reduces neuronal and behavioral responses to visual stimuli
Iurilli et al. examined the interplay between sensory modalities and discovered that auditory cortex activation can inhibit visual cortical neurons via cortico-cortical inputs that activate inhibitory subcircuits originating in the deep layers of the visual cortex.