Cellular mechanisms in the vulnerability to depression and response to antidepressants.

As a testable heuristic, the concept of stress response and adaptation is highly appealing, and the support for the concept is strong. This explanatory model of depression may account for hitherto apparently discordant facts--contradictory symptoms, antidepressant drugs that act on differing systems, facilitation of antidepressant response by augmentation, and response to psychotherapy and pharmacotherapy. This article has focused narrowly on specific cellular elements of the stress-adaptational mechanisms, including the AC-PKA and PLC-PKC transductional cascades, together with specific response elements, such as the HPA axis, BDNF, and NMDA receptors; however, other important mechanisms, including specific receptor subtypes (e.g., 5-HT1A and NE alpha 2), transmitter systems (e.g., acetylcholine and depamine), and hormones (e.g., thyroid and growth hormones and prolactin), which may be important, have not been discussed. As the complex interactions of these systems gradually yield to investigation, not only will new treatments be developed, but better matching of treatment to patient may become an achievable goal.     

Neuronal integration mechanisms have little effect on spike auto-correlations of cortical neurons.

Cortical neurons of behaving animals generate irregular spike sequences, but the sequences generally differ from an entirely random sequence (Poisson process), and they have temporal correlations (spike auto-correlations). Temporally correlated spike sequences can be brought about because of incoming synaptic inputs to the neuron, or because of the neuronal integration mechanism. In this paper, we attempt to determine which is the origin of spike auto-correlations observed in the spiking data recorded from neurons in the prefrontal cortex of a monkey preserving a cue information in the delay response task experiment. Each incoming input is assumed to be independent from its own spike events, and the temporal integration in the neuron is assumed to be reset by every spike event. So, the process to spike is assumed to be divided into two processes: the process independent from its own spikes, which drives the process reset by its own spikes. Under these assumptions, it is found that the spike-independent process needs to have temporal correlations, through examinations of two kinds of correlation coefficient of consecutive inter-spike intervals. It is also found that the spike-reset process has little effect on the spike auto-correlations and the interval distributions. This suggests that the spike auto-correlation does originate in the temporal correlation of incoming synaptic inputs and the neuronal integration mechanism has little effect on the spike auto-correlation.     

Cellular mechanisms of the trigeminally evoked startle response

The startle response is an important mammalian model for studying the cellular mechanisms of emotions and of learning. It consists of contractions of facial and skeletal muscles in response to sudden acoustic, tactile or vestibular stimuli. Whereas the acoustic startle pathway is well described, only a few recent studies have investigated the tactile startle pathway. It was proposed that there is a direct projection from the principal sensory nucleus to the central sensorimotor interface of the startle response, which is formed by the giant neurons in the caudal pontine reticular formation. We explored this projection in greater detail in vitro. Anterograde tracing in rat brain slices confirmed projections with large axon terminals from the ventral part of the principal sensory nucleus to the lateral caudal pontine reticular formation. Electrophysiological studies revealed a monosynaptic glutamatergic connection between principal sensory nucleus neurons and caudal pontine reticular formation giant neurons. The synapses displayed paired-pulse facilitation at high-frequency stimulation, and homosynaptic depression at 1 Hz stimulation. The latter form of plasticity is thought to underlie habituation of the startle response. Furthermore, postsynaptic currents in caudal pontine reticular formation giant neurons evoked by principal sensory nucleus neuron stimulation summed in a linear way with signals evoked by stimulation of auditory afferents. Synaptic plasticity and summation of synaptic currents correspond well with in vivo data previously published by other groups. We thus presume that these synapses mediate trigeminal input to the startle pathway.     

Comparison of the heat shock response in cultured cortical neurons and astrocytes.

Cultured cortical neurons and astrocytes were compared for synthesis of the major inducible 68 kDa heat shock protein. By one- and two-dimensional electrophoresis the inducible 68 kDa protein appeared similar, but astrocytes produced greater amounts of the protein by 3 h than did neurons. Antibodies raised against HeLa cell inducible 72 and constitutive 73 kDa heat shock proteins were used to characterizes the inducible heat shock proteins in neurons and astrocytes. Unlike the gels, major differences were noted of the major inducible heat shock protein in astrocytes compared with neurons when analyzed by Western immunoblots. Heat shock protein 68 kDa mRNA induction in neurons was less than astrocytes suggesting an attenuated inducible 68 kDa heat shock protein response in neurons. The neuronal protein may be a different isoform of the 70 kDa family of heat shock proteins.     

Sensory response enhancement and suppression of monkey primary somatosensory cortical neurons.

Vibratory stimulus-related responses were recorded from monkey primary somatosensory cortical (SI) neurons while animals performed two tasks. In the movement task, vibratory stimuli served as the go-cue for wrist flexion or extension. In the no-movement task, movements normally made in response to vibratory stimuli were extinguished. Area 3a, 3b, and 1 neurons with deep receptive fields (RFs) exhibited greater stimulus-related activity during the movement task than during the no-movement task. Area 3b neurons with cutaneous RFs were similarly enhanced during the movement task, whereas area 1 neurons with cutaneous RFs were less responsive to vibratory stimuli during the movement task. These results suggest that motor-set and/or selective attention may modulate the responsiveness of SI neurons to peripheral stimuli and that changes in sensory responsiveness in SI neurons differ as a function of their cortical location and RF type.     

Intracellular response of caudate neurons to variable frequency stimulation of motor cortical areas in dog

The intracellular response to electrical stimulation of motor cortex was studied in 77 neurons recorded in the head of the caudate (Cd) nucleus of dog. Single pulse stimulation of either medial, intermediate or lateral precruciate cortex produced a response in 69 neurons, 59% of which responded to more than one cortical area. Most intracellular responses were complex potentials consisting of an initial depolarization (E) followed by a longer duration hyperpolarization (I) or E-I response complex. When stimulated with trains of low frequency pulses (10 Hz), the stimulus-generated I potentials reduced the absolute amplitude of the evoked E's, often to a level below resting potential. However, at higher frequencies (50 Hz), the I potentials were attenuated and the E potentials summated into a prolonged depolarization lasting the duration of the stimulus train. A computer model of the response to multiple stimuli was generated assuming that the E-I response to each stimulus pulse in the train should temporally summate with previous responses. As the frequency of stimulation was increased, this model consistently predicted greater summation of the I potentials than was experimentally observed. These data suggest that inhibition of Cd neurons is input frequency dependent such that as the frequency of cortical input increases there is a decrease of input-generated inhibition of Cd neurons. Thus, inhibition may modulate the response of Cd neurons such that cortical input must reach a critical firing frequency before being relayed through the Cd nucleus.     

Excitatory response of prefrontal cortical fast-spiking interneurons to ventral tegmental area stimulation in vivo

Prefrontal cortical (PFC) pyramidal neurons (PN) and fast spiking interneurons (FSI) receive dopaminergic (DA) and non-DA inputs from the ventral tegmental area (VTA). Although the responses of PN to VTA stimulation and DA administration have been extensively studied, little is known about the response of FSI to mesocortical activation. We explored this issue using single and double in vivo juxtacellular recordings of medial PFC PN and FSI with chemical VTA stimulation. Electrophysiological characteristics combined with Neurobiotin staining and parvalbumin immunohistochemistry allowed identification of recorded cells as FSI or PN. NMDA injection into the VTA increased firing in all FSI tested (n = 7), whereas most PN (7/11) responded with an inhibition. Furthermore, FSI excitation matching the temporal course of PN inhibition was observed with FSI-PN paired recordings (n = 5). These divergent electrophysiological responses to mesocortical activation could reflect PFC GABAergic interneurons contributing to silencing PN. Thus, the mesocortical system could provide a critical control of PFC circuits by simultaneously affecting FSI and PN firing.     

Factors contributing to neurotrophin-independent survival of adult sensory neurons

Dorsal root ganglion (DRG) sensory neurons become less dependent upon neurotrophins for their survival as they mature. DRG neurons from young adult rats were dissociated and cultured in vitro in serum-free defined medium. We show that adult DRG sensory neurons are able to survive for at least 2 weeks in culture in the absence of nerve growth factor (NGF). We then investigated potential mechanisms contributing to this apparent neurotrophin-independent survival in these neurons through the use of inhibitors of cellular signaling pathways. The phosphoinositide kinase-3 (PI 3-K) inhibitor LY294002, and a protein kinase C (PKC) inhibitor, chelerythrine resulted in significant decreases in neuronal survival. Neither the mitogen activated protein kinase kinase (MEK) inhibitor U0126 nor two other PKC inhibitors (bisindolylmaleimide and rottlerin) had any significant effect on survival. Our results point to the importance of PI 3-K and PKC signaling in the neurotrophin-independent survival of adult DRG neurons.     

In vivo mechanisms of cortical network dysfunction induced by systemic inflammation

Peripheral inflammation is known to impact brain function, resulting in lethargy, loss of appetite and impaired cognitive abilities. However, the channels for information transfer from the periphery to the brain, the corresponding signaling molecules and the inflammation-induced interaction between microglia and neurons remain obscure. Here, we used longitudinal in vivo two-photon Ca²⁺ imaging to monitor neuronal activity in the mouse cortex throughout the early (initiation) and late (resolution) phases of peripheral inflammation. Single peripheral lipopolysaccharide injection induced a substantial but transient increase in ongoing neuronal activity, restricted to the initiation phase, whereas the impairment of visual processing was selectively observed during the resolution phase of systemic inflammation. In the frontal/motor cortex, the initiation phase-specific cortical hyperactivity was seen in the deep (layer 5) and superficial (layer 2/3) pyramidal neurons but not in the axons coming from the somatosensory cortex, and was accompanied by reduced activity of layer 2/3 cortical interneurons. Moreover, the hyperactivity was preserved after depletion of microglia and in NLRP3^−/− mice but absent in TNF-α^−/− mice. Together, these data identify microglia-independent and TNF-α-mediated reduction of cortical inhibition as a likely cause of the initiation phase-specific cortical hyperactivity and reveal the resolution phase-specific impairment of sensory processing, presumably caused by activated microglia.     

Psychological mechanisms in acute response to trauma.

Traumatic events are common, but posttraumatic stress disorder (PTSD) is relatively rare. These facts have prompted several questions: What variables increase risk for PTSD among trauma-exposed people? Can we distinguish between pathologic and nonpathologic responses to traumatic stressors? If so, what psychobiological mechanisms mediate pathologic responses? Prospective studies have identified certain individual difference variables as heightening risk (e.g., lower intelligence, negative personality traits). Studies on peritraumatic and acute-phase response have identified certain dissociative symptoms (e.g., time slowing, derealization) and cognitive appraisal (e.g., belief that one is about to die) as harbingers of later PTSD. Negative appraisal of acute symptoms themselves may foster chronic morbidity (e.g., that symptoms signify shameful moral weakness or prefigure impending psychosis). Further attempts to elucidate pathologic mechanisms in the cognitive psychology laboratory and via biological challenges are warranted.     

Norepinephrine activates extracellular-regulated kinase in cortical neurons.

BACKGROUND: Previous studies demonstrate that indirect activation of monoamine receptors by antidepressant treatment increases neurotrophic factors that activate the mitogen-activated protein kinase cascade; however, it is also possible that these monoamine receptors influence the mitogen-activated protein kinase pathway independent of neurotrophic factors. The influence of norepinephrine on the phosphorylation of extracellular-regulated protein kinase is characterized. METHODS: Primary cerebral cortical cultures were prepared from embryonic day 18 rat brains and were subsequently incubated with norepinephrine in the absence or presence of agents acting as noradrenergic receptors or as intracellular signaling proteins. Levels of phosphorylated extracellular-regulated protein kinase were determined by immunoblot. RESULTS: The results demonstrate that incubation with norepinephrine produces a time- and dose-dependent activation of phosphorylated extracellular-regulated protein kinase and that this increase is dependent on activation of alpha(2)- and beta-adrenergic receptor subtypes. In addition, the results demonstrate that norepinephrine activation of phosphorylated extracellular-regulated protein kinase is dependent on a pertussis toxin-sensitive G protein, a receptor tyrosine kinase, and activation of phosphatidylinositol 3-kinase. CONCLUSIONS: The findings suggest that activation of the mitogen-activated protein kinase cascade by norepinephrine can occur via a tyrosine kinase-dependent signaling pathway but independent of classical second-messenger or Src-dependent kinases.     

VEGF protein associates to neurons in remote regions following cortical infarct.

Vascular endothelial growth factor (VEGF) is thought to contribute to both neuroprotection and angiogenesis after stroke. While increased expression of VEGF has been demonstrated in animal models after experimental ischemia, these studies have focused almost exclusively on the infarct and peri-infarct regions. The present study investigated the association of VEGF to neurons in remote cortical areas at three days after an infarct in primary motor cortex (M1). Although these remote areas are outside of the direct influence of the ischemic injury, remote plasticity has been implicated in recovery of function. For this study, intracortical microstimulation techniques identified primary and premotor cortical areas in a non-human primate. A focal ischemic infarct was induced in the M1 hand representation, and neurons and VEGF protein were identified using immunohistochemical procedures. Stereological techniques quantitatively assessed neuronal-VEGF association in the infarct and peri-infarct regions, M1 hindlimb, M1 orofacial, and ventral premotor hand representations, as well as non-motor control regions. The results indicate that VEGF protein significantly increased association to neurons in specific remote cortical areas outside of the infarct and peri-infarct regions. The increased association of VEGF to neurons was restricted to cortical areas that are functionally and/or behaviorally related to the area of infarct. There was no significant increase in M1 orofacial region or in non-motor control regions. We hypothesize that enhancement of neuronal VEGF in these functionally related remote cortical areas may be involved in recovery of function after stroke, through either neuroprotection or the induction of remote angiogenesis.     

Central neural mechanisms contributing to the perception of tactile roughness

This paper summarizes recent work showing that tactile roughness appreciation increases in a nearly linear fashion as tactile element spacing or spatial period (SP, distance centre-to-centre between raised dots in these experiments) is increased from 1.5 to 8.5 mm. Although a previous study had reported a U-shaped psychophysical function peaking at a nominal SP of 3.2 mm, differences in the surfaces (including changing SP in only one dimension as compared with two and higher dot heights that minimized contact with the smooth floor) likely contributed to the difference in the results. Roughness estimates were also unaffected by a 2-fold change in scanning speed (50 vs. 95 mm/s). Parallel recordings from neurones in primary somatosensory cortex (SI) during a texture discrimination task indicate that the discharge frequency of many SI cells shows a monotonic relation with SP (up to 5 mm tested). For some cells, the texture signals were ambiguous because discharge frequency co-varied with both texture and the scanning speed, as has also been reported for the peripheral mechanoreceptors that are activated by textured surfaces. Yet other SI cells showed a speed-invariant response to surface texture, consistent with perceptual constancy for roughness over a range of scanning speeds. We suggest that such a discharge pattern could be based on a simple intensive, or mean rate, code: an invariant central representation of surface texture could be obtained by subtracting a speed-varying signal from the ambiguous signals that co-vary with roughness and speed.     

Neuroendocrine mechanisms contributing to the coevolution of sociality and communication

Communication is inherently social, so signaling systems should evolve with social systems. The ‘social complexity hypothesis’ posits that social complexity necessitates communicative complexity and is generally supported in vocalizing mammals. This hypothesis, however, has seldom been tested outside the acoustic modality, and comparisons across studies are confounded by varying definitions of complexity. Moreover, proximate mechanisms underlying coevolution of sociality and communication remain largely unexamined. In this review, we argue that to uncover how sociality and communication coevolve, we need to examine variation in the neuroendocrine mechanisms that coregulate social behavior and signal production and perception. Specifically, we focus on steroid hormones, monoamines, and nonapeptides, which modulate both social behavior and sensorimotor circuits and are likely targets of selection during social evolution. Lastly, we highlight weakly electric fishes as an ideal system in which to comparatively address the proximate mechanisms underlying relationships between social and signal diversity in a novel modality.     

Postsynaptic variability of firing in rat cortical neurons: the roles of input synchronization and synaptic NMDA receptor conductance.

Neurons in the functioning cortex fire erratically, with highly variable intervals between spikes. How much irregularity comes from the process of postsynaptic integration and how much from fluctuations in synaptic input? We have addressed these questions by recording the firing of neurons in slices of rat visual cortex in which synaptic receptors are blocked pharmacologically, while injecting controlled trains of unitary conductance transients, to electrically mimic natural synaptic input. Stimulation with a Poisson train of fast excitatory (AMPA-type) conductance transients, to simulate independent inputs, produced much less variability than encountered in vivo. Addition of NMDA-type conductance to each unitary event regularized the firing but lowered the precision and reliability of spikes in repeated responses. Independent Poisson trains of GABA-type conductance transients (reversing at the resting potential), which simulated independent activity in a population of presynaptic inhibitory neurons, failed to increase timing variability substantially but increased the precision of responses. However, introduction of synchrony, or correlations, in the excitatory input, according to a nonstationary Poisson model, dramatically raised timing variability to in vivo levels. The NMDA phase of compound AMPA-NMDA events conferred a time-dependent postsynaptic variability, whereby the reliability and precision of spikes degraded rapidly over the 100 msec after the start of a synchronous input burst. We conclude that postsynaptic mechanisms add significant variability to cortical responses but that substantial synchrony of inputs is necessary to explain in vivo variability. We suggest that NMDA receptors help to implement a switch from precise firing to random firing during responses to concerted inputs.