Potentiation of cortical inhibition by visual deprivation

The fine-tuning of circuits in sensory cortex requires sensory experience during an early critical period. Visual deprivation during the critical period has catastrophic effects on visual function, including loss of visual responsiveness to the deprived eye, reduced visual acuity, and loss of tuning to many stimulus characteristics. These changes occur faster than the remodelling of thalamocortical axons, but the intracortical plasticity mechanisms that underlie them are incompletely understood. Long-term depression of excitatory intracortical synapses has been proposed as a general candidate mechanism for the loss of cortical responsiveness after visual deprivation. Alternatively (or in addition), the decreased ability of the deprived eye to activate cortical neurons could be due to enhanced intracortical inhibition. Here we show that visual deprivation leaves excitatory connections in layer 4 (the primary input layer to cortex) unaffected, but markedly potentiates inhibitory feedback between fast-spiking basket cells (FS cells) and star pyramidal neurons (star pyramids). Further, a previously undescribed form of long-term potentiation of inhibition (LTPi) could be induced at synapses from FS cells to star pyramids, and was occluded by previous visual deprivation. These data suggest that potentiation of inhibition is a major cellular mechanism underlying the deprivation-induced degradation of visual function, and that this form of LTPi is important in fine-tuning cortical circuitry in response to visual experience.     

Modulation of visual cortical plasticity by acetylcholine and noradrenaline

During a critical period of postnatal development, the temporary closure of one eye in kittens will permanently shift the ocular dominance (OD) of neurones in the striate cortex to the eye that remains open. The OD plasticity can be substantially reduced if the cortex is infused continuously with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) during the period of monocular deprivation, an effect that has been attributed to selective depletion of cortical noradrenaline. However, several other methods causing noradrenaline (NA) depletion leave the plasticity intact. Here we present a possible explanation for the conflicting results. Combined destruction of the cortical noradrenergic and cholinergic innervations reduces the physiological response to monocular deprivation although lesions of either system alone are ineffective. We also find that 6-OHDA can interfere directly with the action of acetylcholine (ACh) on cortical neurones. Taken together, our results suggest that intracortical 6-OHDA disrupts plasticity by interfering with both cholinergic and noradrenergic transmission and raise the possibility that ACh and NA facilitate synaptic modifications in the striate cortex by a common molecular mechanism.     

Selective gating of visual signals by microstimulation of frontal cortex

Several decades of psychophysical and neurophysiological studies have established that visual signals are enhanced at the locus of attention. What remains a mystery is the mechanism that initiates biases in the strength of visual representations. Recent evidence argues that, during spatial attention, these biases reflect nascent saccadic eye movement commands. We examined the functional interaction of saccade preparation and visual coding by electrically stimulating sites within the frontal eye fields (FEF) and measuring its effect on the activity of neurons in extrastriate visual cortex. Here we show that visual responses in area V4 could be enhanced after brief stimulation of retinotopically corresponding sites within the FEF using currents below that needed to evoke saccades. The magnitude of the enhancement depended on the effectiveness of receptive field stimuli as well as on the presence of competing stimuli outside the receptive field. Stimulation of non-corresponding FEF representations could suppress V4 responses. The results suggest that the gain of visual signals is modified according to the strength of spatially corresponding eye movement commands.     

A cellular analogue of visual cortical plasticity

Neuronal activity plays an important role in the development of the visual pathway. The modulation of synaptic transmission by temporal correlation between pre- and postsynaptic activity is one mechanism which could underly visual cortical plasticity. We report here that functional changes in single neurons of area 17, analogous to those known to take place during epigenesis of visual cortex, can be induced experimentally during the time of recording. This was done by a differential pairing procedure, during which iontophoresis was used to artificially increase the visual response for a given stimulus, and to decrease (or block) the response for a second stimulus which differed in ocularity or orientation. Long-term modifications in ocular dominance and orientation selectivity were produced in 33% and 43% of recorded cells respectively. Neuronal selectivity was nearly always displaced towards the stimulus paired with the reinforced visual response. The largest changes were obtained at the peak of the critical period in normally reared and visually deprived kittens, but changes were also observed in adults. Our findings support the role of temporal correlation between pre- and postsynaptic activity in the induction of long-lasting modifications of synaptic transmission during development, and in associative learning.     

Spontaneously emerging cortical representations of visual attributes

Spontaneous cortical activity--ongoing activity in the absence of intentional sensory input--has been studied extensively, using methods ranging from EEG (electroencephalography), through voltage sensitive dye imaging, down to recordings from single neurons. Ongoing cortical activity has been shown to play a critical role in development, and must also be essential for processing sensory perception, because it modulates stimulus-evoked activity, and is correlated with behaviour. Yet its role in the processing of external information and its relationship to internal representations of sensory attributes remains unknown. Using voltage sensitive dye imaging, we previously established a close link between ongoing activity in the visual cortex of anaesthetized cats and the spontaneous firing of a single neuron. Here we report that such activity encompasses a set of dynamically switching cortical states, many of which correspond closely to orientation maps. When such an orientation state emerged spontaneously, it spanned several hypercolumns and was often followed by a state corresponding to a proximal orientation. We suggest that dynamically switching cortical states could represent the brain's internal context, and therefore reflect or influence memory, perception and behaviour.     

Imaging cortical correlates of illusion in early visual cortex

Exploring visual illusions reveals fundamental principles of cortical processing. Illusory motion perception of non-moving stimuli was described almost a century ago by Gestalt psychologists. However, the underlying neuronal mechanisms remain unknown. To explore cortical mechanisms underlying the 'line-motion' illusion, we used real-time optical imaging, which is highly sensitive to subthreshold activity. We examined, in the visual cortex of the anaesthetized cat, responses to five stimuli: a stationary small square and a long bar; a moving square; a drawn-out bar; and the well-known line-motion illusion, a stationary square briefly preceding a long stationary bar presentation. Whereas flashing the bar alone evoked the expected localized, short latency and high amplitude activity patterns, presenting a square 60-100 ms before a bar induced the dynamic activity patterns resembling that of fast movement. The preceding square, even though physically non-moving, created gradually propagating subthreshold cortical activity that must contribute to illusory motion, because it was indistinguishable from cortical representations of real motion in this area. These findings demonstrate the effect of spatio-temporal patterns of subthreshold synaptic potentials on cortical processing and the shaping of perception.     

Network anatomy and in vivo physiology of visual cortical neurons

In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.     

A subset of dopamine neurons signals reward for odour memory in Drosophila

Animals approach stimuli that predict a pleasant outcome. After the paired presentation of an odour and a reward, Drosophila melanogaster can develop a conditioned approach towards that odour. Despite recent advances in understanding the neural circuits for associative memory and appetitive motivation, the cellular mechanisms for reward processing in the fly brain are unknown. Here we show that a group of dopamine neurons in the protocerebral anterior medial (PAM) cluster signals sugar reward by transient activation and inactivation of target neurons in intact behaving flies. These dopamine neurons are selectively required for the reinforcing property of, but not a reflexive response to, the sugar stimulus. In vivo calcium imaging revealed that these neurons are activated by sugar ingestion and the activation is increased on starvation. The output sites of the PAM neurons are mainly localized to the medial lobes of the mushroom bodies (MBs), where appetitive olfactory associative memory is formed. We therefore propose that the PAM cluster neurons endow a positive predictive value to the odour in the MBs. Dopamine in insects is known to mediate aversive reinforcement signals. Our results highlight the cellular specificity underlying the various roles of dopamine and the importance of spatially segregated local circuits within the MBs.     

Lateral habenula as a source of negative reward signals in dopamine neurons

Midbrain dopamine neurons are key components of the brain's reward system, which is thought to guide reward-seeking behaviours. Although recent studies have shown how dopamine neurons respond to rewards and sensory stimuli predicting reward, it is unclear which parts of the brain provide dopamine neurons with signals necessary for these actions. Here we show that the primate lateral habenula, part of the structure called the epithalamus, is a major candidate for a source of negative reward-related signals in dopamine neurons. We recorded the activity of habenula neurons and dopamine neurons while rhesus monkeys were performing a visually guided saccade task with positionally biased reward outcomes. Many habenula neurons were excited by a no-reward-predicting target and inhibited by a reward-predicting target. In contrast, dopamine neurons were excited and inhibited by reward-predicting and no-reward-predicting targets, respectively. Each time the rewarded and unrewarded positions were reversed, both habenula and dopamine neurons reversed their responses as the bias in saccade latency reversed. In unrewarded trials, the excitation of habenula neurons started earlier than the inhibition of dopamine neurons. Furthermore, weak electrical stimulation of the lateral habenula elicited strong inhibitions in dopamine neurons. These results suggest that the inhibitory input from the lateral habenula plays an important role in determining the reward-related activity of dopamine neurons.     

Clonally related visual cortical neurons show similar stimulus feature selectivity

A fundamental feature of the mammalian neocortex is its columnar organization. In the visual cortex, functional columns consisting of neurons with similar orientation preferences have been characterized extensively, but how these columns are constructed during development remains unclear. The radial unit hypothesis posits that the ontogenetic columns formed by clonally related neurons migrating along the same radial glial fibre during corticogenesis provide the basis for functional columns in adult neocortex. However, a direct correspondence between the ontogenetic and functional columns has not been demonstrated. Here we show that, despite the lack of a discernible orientation map in mouse visual cortex, sister neurons in the same radial clone exhibit similar orientation preferences. Using a retroviral vector encoding green fluorescent protein to label radial clones of excitatory neurons, and in vivo two-photon calcium imaging to measure neuronal response properties, we found that sister neurons preferred similar orientations whereas nearby non-sister neurons showed no such relationship. Interestingly, disruption of gap junction coupling by viral expression of a dominant-negative mutant of Cx26 (also known as Gjb2) or by daily administration of a gap junction blocker, carbenoxolone, during the first postnatal week greatly diminished the functional similarity between sister neurons, suggesting that the maturation of ontogenetic into functional columns requires intercellular communication through gap junctions. Together with the recent finding of preferential excitatory connections among sister neurons, our results support the radial unit hypothesis and unify the ontogenetic and functional columns in the visual cortex.     

Selective responses of visual cortical cells do not depend on shunting inhibition

Theoretical analyses of the electrical behaviour of the highly branched processes of nerve cells has focused attention on the possibility that single cells perform complex logical operations rather than simply summing their synaptic inputs. In particular, it has been suggested that the orientation and direction selectivity of cells in the visual cortex results from the action of a nonlinear 'shunting' inhibition that emulates an AND-NOT logical operation. The characteristic biophysical feature of this proposed inhibitory mechanism is that it evokes a large and relatively sustained increase in the conductance of the neuronal membrane while leaving the membrane potential unaffected. This shunting mechanism contrasts with linear 'summative' inhibition in which conductance changes are less prominent, and inhibition is achieved by hyperpolarization of the membrane potential. In a direct experimental test of the hypothesis that the selectivity of visual cortical neurons depends on shunting inhibition we found no evidence for the large conductance changes predicted by the theory.     

Objective analysis of the topological organization of the primate cortical visual system.

The primate cortical visual system is composed of many structurally and functionally distinct areas, each receiving and sending about 10 projections from and to other cortical areas. The visual cortex is thus served by many cortico-cortical connections to form a network of considerable complexity. Thus the gross organization of this cortical processing system presents a formidable topological problem: although the spatial position of the areas in the brain is reasonably well established, the gross 'processing architecture' defined by the connections, is less well understood. Here I report an optimization approach that gives both qualitative and quantitative insight into the connectional topology of the primate cortical visual system. This approach supports suggestions that the system is divided into a dorsal 'stream' and a ventral 'stream' with limited cross-talk, that these two streams reconverge in the region of the principal sulcus (area 46) and in the superior temporal polysensory areas, that the system is hierarchically organized, and that the majority of the connections are from 'nearest-neighbour' and 'next-door-but-one' areas.     

Mixed parvocellular and magnocellular geniculate signals in visual area V4.

Visual information from the retina is transmitted to the cerebral cortex by way of the lateral geniculate nucleus (LGN) in the thalamus. In primates, most of the retinal ganglion cells that project to the LGN belong to one of two classes, P and M, whose axons terminate in the parvocellular or magnocellular subdivisions of the LGN. These cell classes give rise to two channels that have been distinguished anatomically, physiologically and behaviourally. The visual cortex also can be subdivided into two pathways, one specialized for motion processing and the other for colour and form information. Several lines of indirect evidence have suggested a close correspondence between the subcortical and cortical pathways, such that the M channel provides input to the motion pathway and the P channel drives the colour/form pathway. This hypothesis was tested directly by selectively inactivating either the magnocellular or parvocellular subdivision of the LGN and recording the effects on visual responses in the cortex. We have previously reported that, in accordance with the hypothesis, responses in the motion pathway in the cortex depend primarily on magnocellular LGN. We now report that in the colour/form pathway, visual responses depend on both P and M input. These results argue against a simple correspondence between the subcortical and cortical pathways.     

Experience with moving visual stimuli drives the early development of cortical direction selectivity

The onset of vision occurs when neural circuits in the visual cortex are immature, lacking both the full complement of connections and the response selectivity that defines functional maturity. Direction-selective responses are particularly vulnerable to the effects of early visual deprivation, but it remains unclear how stimulus-driven neural activity guides the emergence of cortical direction selectivity. Here we report observations from a motion training protocol that allowed us to monitor the impact of experience on the development of direction-selective responses in visually naive ferrets. Using intrinsic signal imaging techniques, we found that training with a single axis of motion induced the rapid emergence of direction columns that were confined to cortical regions preferentially activated by the training stimulus. Using two-photon calcium imaging techniques, we found that single neurons in visually naive animals exhibited weak directional biases and lacked the strong local coherence in the spatial organization of direction preference that was evident in mature animals. Training with a moving stimulus, but not with a flashed stimulus, strengthened the direction-selective responses of individual neurons and preferentially reversed the direction biases of neurons that deviated from their neighbours. Both effects contributed to an increase in local coherence. We conclude that early experience with moving visual stimuli drives the rapid emergence of direction-selective responses in the visual cortex.     

电刺激大鼠mPFC对听皮层神经元听反应的影响

实验在40只成年SD大鼠上进行,使用常规电生理学方法,观察了电刺激大鼠内侧额叶前皮质(medial prefrontal cortex, mPFC)对听皮层神经元听反应的影响.在122个神经元上观察了电刺激mPFC对听反应的影响.对其中93个神经元作了详细分析发现,有73个神经元的听反应受到易化（39个,41.9%）或抑制（34个,36.6%）.刺激mPFC对听反应的影响存在最佳刺激间隔,大多数神经元（51个,69%）在10~15 ms之间.结果提示,大鼠mPFC可对听皮层神经元的听反应调制,这种调制可能是通过多级神经元环路实现的.     

An evolutionary scaling law for the primate visual system and its basis in cortical function

A hallmark of mammalian brain evolution is the disproportionate increase in neocortical size as compared with subcortical structures. Because primary visual cortex (V1) is the most thoroughly understood cortical region, the visual system provides an excellent model in which to investigate the evolutionary expansion of neocortex. I have compared the numbers of neurons in the visual thalamus (lateral geniculate nucleus; LGN) and area V1 across primate species. Here I find that the number of V1 neurons increases as the 3/2 power of the number of LGN neurons. As a consequence of this scaling law, the human, for example, uses four times as many V1 neurons per LGN neuron (356) to process visual information as does a tarsier (87). I argue that the 3/2 power relationship is a natural consequence of the organization of V1, together with the requirement that spatial resolution in V1 should parallel the maximum resolution provided by the LGN. The additional observation that thalamus/neocortex follows the same evolutionary scaling law as LGN/V1 may suggest that neocortex generally conforms to the same organizational principle as V1.