Hippocampal CA3 and CA2 have distinct bilateral innervation patterns to CA1 in rodents

Ipsilateral and contralateral hippocampal CA3-CA1 and CA2-CA1 projections were investigated in adult male Long-Evans rats by retrograde tracing. Injection of the retrograde tracer cholera toxin subunit B in the strata oriens and radiatum of dorsal CA1 resulted in labeling of predominantly pyramidal cells in ipsilateral and contralateral CA3 and CA2. The contralateral and ipsilateral anterior-posterior extents of CA3 innervation to CA1 were similar. Fifteen to twenty per cent of the hippocampus proper cells that give rise to CA1 stratum oriens innervation were CA2 pyramidal cells, whereas CA2 cells were a mere 3% for CA1 stratum radiatum innervation. The preferred projection of CA2 pyramidal cells to the CA1 stratum oriens was also manifested in transgenic mice that express GFP under the control of the CACNG5 promoter, in which CA2 cells express high amounts of GFP. The ratios of ipsilateral to contralateral projections were compared. For the CA3-CA1 connection, we found that dorsal CA1 stratum radiatum received more ipsilateral projections whereas CA1 stratum oriens received more contralateral innervation. Interestingly, ipsilateral connections dominated for both CA2-CA1 stratum oriens and CA2-CA1 stratum radiatum. These results demonstrate that the primary intrahippocampal target of CA2 pyramidal cells is the ipsilateral CA1 stratum oriens, in contrast to CA3 cells which project more diversely to bilateral CA1 regions. Such innervation patterns may suggest differential dendritic information processing in apical and basal dendrites of CA1 pyramidal cells.     

Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network.

The CA3 network in the hippocampus may operate as an autoassociator, in which declarative memories, known to be dependent on hippocampal processing, could be stored, and subsequently retrieved, using modifiable synaptic efficacies in the CA3 recurrent collateral system. On the basis of this hypothesis, the authors explore the computational relevance of the extrinsic afferents to the CA3 network. A quantitative statistical analysis of the information that may be relayed by such afferent connections reveals the need for two distinct systems of input synapses. The synapses of the first system need to be strong (but not associatively modifiable) in order to force, during learning, the CA3 cells into a pattern of activity relatively independent of any inputs being received from the recurrent collaterals, and which thus reflects sizable amounts of new information. It is proposed that the mossy fiber system performs this function. A second system, with a large number of associatively modifiable synapses on each receiving cell, is needed in order to relay a signal specific enough to initiate the retrieval process. This may be identified, we propose, with the perforant path input to CA3.     

Oxygen consumption rates during three different neuronal activity states in the hippocampal CA3 network

The brain is an organ with high metabolic rate. However, little is known about energy utilization during different activity states of neuronal networks. We addressed this issue in area CA3 of hippocampal slice cultures under well-defined recording conditions using a 20% O₂ gas mixture. We combined recordings of local field potential and interstitial partial oxygen pressure (pO₂) during three different activity states, namely fast network oscillations in the gamma-frequency band (30 to 100 Hz), spontaneous network activity and absence of spiking (action potentials). Oxygen consumption rates were determined by pO₂ depth profiles with high spatial resolution and a mathematical model that considers convective transport, diffusion, and activity-dependent consumption of oxygen. We show that: (1) Relative oxygen consumption rate during cholinergic gamma oscillations was 2.2-fold and 5.3-fold higher compared with spontaneous activity and absence of spiking, respectively. (2) Gamma oscillations were associated with a similar large decrease in pO₂ as observed previously with a 95% O₂ gas mixture. (3) Sufficient oxygenation during fast network oscillations in vivo is ensured by the calculated critical radius of 30 to 40 μm around a capillary. We conclude that the structural and biophysical features of brain tissue permit variations in local oxygen consumption by a factor of about five.     

Deterministic and stochastic identification of neurophysiologic systems

The paper deals with deterministic and stochastic identification methods applied to the concrete neurophysiological systems. The deterministic identification was carried out for the system: efferent fibres-muscle. The obtained transition characteristics demonstrated dynamic nonlinearity of the system. Identification of the neuronal model and the "afferent fibres-synapses-neuron" system in mollusc Planorbis corneus was carried out using the stochastic methods. For these purpose the Wiener method of stochastic identification was expanded for the case of pulse trains as input and output signals. The weight of the nonlinear component in the Wiener model and accuracy of the model prediction were quantitatively estimated. The results obtained proves the possibility of using these identification methods for various neurophysiological systems.     

CA1 subfield contributions to memory integration and inference

The ability to combine information acquired at different times to make novel inferences is a powerful function of episodic memory. One perspective suggests that by retrieving related knowledge during new experiences, existing memories can be linked to the new, overlapping information as it is encoded. The resulting memory traces would thus incorporate content across event boundaries, representing important relationships among items encountered during separate experiences. While prior work suggests that the hippocampus is involved in linking memories experienced at different times, the involvement of specific subfields in this process remains unknown. Using both univariate and multivariate analyses of high‐resolution functional magnetic resonance imaging (fMRI) data, we localized this specialized encoding mechanism to human CA₁. Specifically, right CA₁ responses during encoding of events that overlapped with prior experience predicted subsequent success on a test requiring inferences about the relationships among events. Furthermore, we employed neural pattern similarity analysis to show that patterns of activation evoked during overlapping event encoding were later reinstated in CA₁ during successful inference. The reinstatement of CA₁ patterns during inference was specific to those trials that were performed quickly and accurately, consistent with the notion that linking memories during learning facilitates novel judgments. These analyses provide converging evidence that CA₁ plays a unique role in encoding overlapping events and highlight the dynamic interactions between hippocampal‐mediated encoding and retrieval processes. More broadly, our data reflect the adaptive nature of episodic memories, in which representations are derived across events in anticipation of future judgments. © 2014 Wiley Periodicals, Inc.     

Synchronous epileptiform bursts without chemical transmission in CA2, CA3 and dentate areas of the hippocampus

Slices of rat hippocampus maintained in a medium containing Mn²⁺ and lowered Ca²⁺ concentration, which demonstrably blocked chemical synapses, generated spontaneous bursts of population spikes in all cell body layers after 30–60 min of incubation. Therefore, electrical interactions alone can synchronize neuronal activity in the hippocampus, and they are probably important during epileptiform events.     

A surgical approach to Holmes' tremor associated with high-frequency synchronous bursts

INTRODUCTION: The effectiveness of thalamic stimulation is now clearly demonstrated for essential tremor, but remains to be demonstrated for other types of tremor. OBSERVATION: A young woman presented Holmes' tremor resulting from a pontine tegmental hemorrhage related to an arteriovenous malformation. A surgical approach was considered when major functional impairment persisted at 2-year follow-up despite drug therapy. The patient underwent unilateral thalamic deep brain stimulation (Vim); major improvement persisted at eighteen months follow-up. CONCLUSION: This observation is in line with previous reports suggesting that thalamic surgery can be one of the best options for treating medically intractable Holmes' tremor. The mechanism underlying the tremor, implying dentate-rubro-thalamic pathways is discussed. Moreover, the patient exhibited short periods of 16Hz tremor when her arms were maintained outstretched. Thalamic stimulation also appears to be effective for these high-frequency synchronous cerebellar bursts.     

Influence of tetramethylenedisulfotetramine on synchronous calcium oscillations at distinct developmental stages of hippocampal neuronal cultures

The spatial and temporal patterns of spontaneous synchronous Ca²⁺ oscillations (SCOs) regulate physiological pathways that influence neuronal development, excitability, and health. Hippocampal neuronal cultures (HN) and neuron/glia co-cultures (HNG) produced from neonatal mice were loaded with Fluo-4/AM and SCOs recorded in real-time using a Fluorescence Imaging Plate Reader at different developmental stages in vitro. HNG showed an earlier onset of SCOs, with low amplitude and low frequency SCOs at 4 days in vitro (DIV), whereas HN were quiescent at this point. SCO amplitude peaked at 9 DIV for both cultures. SCO network frequency peaked at 12 DIV in HN, whereas in HNG the frequency peaked at 6 DIV. SCO patterns were associated with the temporal development of neuronal networks and their ratio of glutamatergic to GABAergic markers of excitatory/inhibitory balance. HN and HNG exhibited differential responses to the convulsant tetramethylenedisulfotetramine (TETS) and were highly dependent on DIV. In HN, TETS triggered an acute rise of intracellular Ca²⁺ (Phase I response) only in 14 DIV and a sustained decrease of SCO frequency with increased amplitude (Phase II response) at all developmental stages. In HNG, TETS decreased the SCO frequency and increased the amplitude at 6 and 14 but not 9 DIV. There was no acute Ca²⁺ rise (Phase I response) in any age of HNG tested with TETS. These data demonstrated the importance of glia and developmental stage in modulating neuronal responses to TETS. Our results illustrate the applicability of the model for investigating how caged convulsants elicit abnormal network activity during the development of HN and HNG cultures in vitro.     

Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury.

Caspases are cysteine proteases that mediate apoptotic death in a variety of cellular systems, including neurons. Caspases are activated through extrinsic or intrinsic pathways. The latter is used by most neurons in most situations. In this pathway, release of mitochondrial cytochrome c into the cytoplasm induces formation of the apoptosome, which leads to the activation of caspase 9 and subsequently other caspases. Recent data demonstrate that when caspase activation is inhibited at or downstream of the apoptosome, neurons undergo a delayed, caspase-independent death. Furthermore, there are instances, most notably following excitotoxic injury and calcium overload, in which the direct cell death pathway elicited differs from classical apoptosis. The molecular and biochemical features of such caspase-independent, nonapoptotic forms of neuronal death are just beginning to be elucidated, but alterations at the level of the mitochondria and noncaspase proteases play significant roles. Mitochondrial alterations in caspase-independent death may include energy depletion, generation of free radicals, opening of the permeability transition pore, and release of cytotoxic proteins, such as apoptosis-inducing factor. The particular mechanisms employed can be context dependent. In disease states, in which a combination of apoptotic and nonapoptotic death occurs, therapeutic strategies need to take into account both caspase-dependent and -independent pathways.     

Synaptic contributions to θ rhythm genesis in rat CA1–CA3 hippocampal pyramidal neurons in vivo

The effects of intracellular Cl⁻ diffusion and hyperpolarizing current pulses on inhibitory postsynaptic potentials (IPSPs) and the transmembrane theta rhythm of CA1–CA3 pyramidal neurons were tested in urethanized and curarized rats. Cl⁻ diffusion and hyperpolarizing currents decreased the amplitude of IPSPs evoked by fornix stimulation without modifying the θ rhythm amplitude and phase. The membrane conductance was typically 22–46% higher at the positive than negative intracellular θ peaks. Results indicate that in curarized rats excitatory postsynaptic potentials were the main components of intracellular θ without an important participation of IPSPs in θ rhythm genesis.     

Different proctolin neurons elicit distinct motor patterns from a multifunctional neuronal network.

Distinct motor patterns are selected from a multifunctional neuronal network by activation of different modulatory projection neurons. Subsets of these projection neurons can contain the same neuromodulator(s), yet little is known about the relative influence of such neurons on network activity. We have addressed this issue in the stomatogastric nervous system of the crab Cancer borealis. Within this system, there is a neuronal network in the stomatogastric ganglion (STG) that produces many versions of the pyloric and gastric mill rhythms. These different rhythms result from activation of different projection neurons that innervate the STG from neighboring ganglia and modulate STG network activity. Three pairs of these projection neurons contain the neuropeptide proctolin. These include the previously identified modulatory proctolin neuron and modulatory commissural neuron 1 (MCN1) and the newly identified modulatory commissural neuron 7 (MCN7). We document here that each of these neurons contains a unique complement of cotransmitters and that each of these neurons elicits a distinct version of the pyloric motor pattern. Moreover, only one of them (MCN1) also elicits a gastric mill rhythm. The MCN7-elicited pyloric rhythm includes a pivotal switch by one STG network neuron from playing a minor to a major role in motor pattern generation. Therefore, modulatory neurons that share a peptide transmitter can elicit distinct motor patterns from a common target network.     

NCX3 knockout mice exhibit increased hippocampal CA1 and CA2 neuronal damage compared to wild-type mice following global cerebral ischemia

There is uncertainty as to whether the plasma membrane Na(+)/Ca(2+)exchanger (NCX) has a neuroprotective or neurodamaging role following cerebral ischemia. To address this issue we compared hippocampal neuronal injury in NCX3 knockout mice (Ncx3(-/-)) and wild-type mice (Ncx3(+/+)) following global cerebral ischemia. Using a bilateral common carotid artery occlusion (BCCAO) model of global ischemia we subjected NCX3 knockout and wild-type mice to 17 and 15 minutes of ischemia. Following the 17 minute period of ischemia, wild-type mice exhibited approximately 80% CA1 neuronal loss and approximately 40% CA2 neuronal loss. In contrast, NCX3 knockout mice displayed >95% CA1 neuronal loss and approximately 95% CA2 neuronal loss. Following the 15 minute period of ischemia, wild-type mice did not exhibit any significant hippocampal neuronal loss. In contrast, NCX3 knockout mice displayed approximately 45% CA1 neuronal loss and approximately 25% CA2 neuronal loss. The results clearly demonstrate that mice deficient in the NCX3 protein are more susceptible to global cerebral ischemia than wild-type mice. Our findings suggest NCX3 has a positive role in maintaining neuronal intracellular calcium homeostasis following ischemia, and that when exchanger function is compromised neurons are more susceptible to calcium deregulation and cell death.     

The activity within the CA3 excitatory network during Theiler's virus encephalitis is distinct from that observed during chronic epilepsy

Viral infections of the central nervous system (CNS) are associated with an increased risk for seizures during the acute infection period and the subsequent development of chronic epilepsy that is often difficult to treat. In previous work, we have shown that mice of the C57BL/6 strain infected with Theiler's murine encephalomyelitis virus (TMEV) exhibit a similar sequence, thereby providing a potential useful model of virus-induced epilepsy. The present study examines spontaneous and miniature excitatory postsynaptic currents in CA3 pyramidal cells recorded from brain slices prepared during both the acute phase during encephalitis and 2 months following TMEV infection. Animals that develop chronic epilepsy following TMEV infection exhibit considerable hippocampal sclerosis, directly implicating this brain region in the process of epileptogenesis. There are significant increases in amplitude and frequency of spontaneous and miniature excitatory currents in CA3 cells recorded in brain slices prepared during the acute infection period and 2 months after infection. However, the patterns of changes observed are markedly different during these two periods, suggesting that there are underlying changes in the network over time. These differences have implications for the treatment used during the acute infection and after chronic seizures develop.     

Haemodynamic response to haemorrhage: distinct contributions of midbrain and forebrain structures

The haemodynamic response to a fixed volume haemorrhage passes through three distinct phases: a normotensive, compensatory phase; a hypotensive, decompensatory phase; and a post-haemorrhage, recompensatory phase. The role of the forebrain and midbrain in regulating the triphasic response to a 'fast' (1.5%/min) or 'slow' (0.75%/min) rate of blood withdrawal (30% haemorrhage) was evaluated by comparing, in unanaesthetised rats, the effects of pre-collicular (PCD) vs. pre-trigeminal decerebrations (PTD). It was found that pre-trigeminal decerebration attenuated the decompensatory (hypotensive) phase to either a fast or slow haemorrhage. In contrast, pre-collicular decerebration attenuated the compensatory and recompensatory phases of the response to a 'fast' (but not a slow) haemorrhage. These results suggest that the integrity of (i) forebrain structure(s) are critical for compensatory and recompensatory responses to 'rapid' blood loss; and (ii) midbrain structure(s) are critical for the decompensatory response to progressive blood loss irrespective of rate.     

Adrenergic receptor modulation of hippocampal CA3 network activity

Norepinephrine (NE) has demonstrated proconvulsant and antiepileptic properties; however, the specific pharmacology of these actions has not been clearly established. To address this, we studied the effect of NE on hippocampal CA3 epileptiform activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations reduced their frequency, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of betaAR blockade, increasing concentrations of NE caused a monophasic decrease in epileptiform activity. Antagonists selective for alpha1 or alpha2ARs were then used to determine which alphaAR type was involved. While discriminating concentrations of the alpha1AR antagonists prazosin and terazosin had no effect, selective amounts of the alpha2AR antagonists RS79948 and RX821002 significantly reduced the potency of NE in decreasing epileptiform activity. Furthermore, this antiepileptic action of NE persisted when all GABA-mediated inhibition was blocked. This data suggests that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 epileptiform activity are mediated primarily via beta and alpha2ARs, respectively. Moreover, our results imply that the antiepileptic effect of alpha2AR activation in CA3 is not dependent on the GABAergic system.     

Synaptic contributions to theta rhythm genesis in rat CA1-CA3 hippocampal pyramidal neurons in vivo

The effects of intracellular Cl- diffusion and hyperpolarizing current pulses on inhibitory postsynaptic potentials (IPSPs) and the transmembrane theta rhythm of CA1-CA3 pyramidal neurons were tested in urethanized and curarized rats. Cl- diffusion and hyperpolarizing currents decreased the amplitude of IPSPs evoked by fornix stimulation without modifying the theta rhythm amplitude and phase. The membrane conductance was typically 22-46% higher at the positive than negative intracellular theta peaks. Results indicate that in curarized rats excitatory postsynaptic potentials were the main components of intracellular theta without an important participation of IPSPs in theta rhythm genesis.     

Methods for characterizing interspike intervals and identifying bursts in neuronal activity

Neurons produce complex patterns of electrical spikes, which are often clustered in bursts. The patterns of spikes and bursts can change substantially when neurons are exposed to toxins and chemical agents. For that reason, characterization of these patterns is important for the development of neuron-based biosensors for environmental threat exposure. Here, we develop a quantitative approach to describe the distribution of interspike intervals, based on plotting histograms of the logarithm of the interspike interval. This approach provides a method for automatically classifying spikes into bursts, which does not depend on assumptions about the burst parameters. Furthermore, the approach provides a sensitive technique for detecting changes in spike and burst patterns induced by pharmacological exposure. Hence, it is suitable for use both as a research tool and for deployment in a neuron-based biosensor.     

海马CA3区联想记忆功能的神经网络建模

背景：海马是一个与记忆相关的重要脑区,在联想记忆中起着关键的作用。海马CA3区是形成联想记忆最重要的脑区,它从功能上被分为自联想记忆和异联想记忆。理解记忆的形成和读取需要建立海马功能的详细模型。 目的：根据海马CA3区的结构,建立一个海马CA3区功能的详细模型。 方法：该模型是一个三层的类Hopfield神经网络,由280个Izhikevich人工神经元组成。以Izhikevich神经元模型做为节点,用Hebbian学习法则调节权值。在给模型的输入加入白噪声的情况下用MATLAB对其仿真。在仿真中,记忆用同步放电序列表示。 结果与结论：仿真结果表明,模型的第三层具有异联想记忆功能;模型的第一层和第二层能完成自联想记忆功能。该模型很好的重现了海马CA3区三个子区域的记忆功能。但真实生物神经网络的功能极其动力学特性不可能通过建立一个简单的模型完全理解。该模型由280个神经元组成,远远小于实际神经元的数量,这也说明所建模型的特性与CA3实际生物神经网络的特性之间还存在很大差距。     

Fitting a stochastic spiking model to neuronal current injection data

Spiking neuron models have advanced to the stage of accurately predicting the spike times of individual biological neurons for given fluctuating current. Most of the successful models are based on deterministic mechanistic modeling. In order to describe the stochastic aspect of neuronal firing, I propose setting a deterministic model in a stochastic framework, namely, incorporating the multi-timescale adaptive threshold (MAT) model of neuronal spiking into the stochastic framework of the linear–nonlinear Poisson (LNP) model in the form of a generalized linear model (GLM). In this setting, the probability of spike occurrence is updated each time a spike is derived from the past probability. Accordingly, the model may account for nontrivial firing patterns of various neurons that cannot be realized with the inhomogeneous Poisson process. The stochastic MAT model is not only capable of characterizing firing mechanisms specific to individual neurons, but may render the statistical inference feasible for the underlying mechanisms from the data. I also examine here two plausible principles for adjusting the model parameters: maximizing the spike time coincidence between the model and data, and maximizing the likelihood. It is found that these principles bring about greatly different characteristics for an identical set of data.